흉선 기능의 억제 - 면역기능의 억제 논문

[문형철]

몸, 마음, 영혼의 탐구

마음(심장)의 에너지가 뇌를 지배하고 

마음의 억압(스트레스반응)은 흉선기능을 억제하여 각종 질병을 일으킨다

https://www.spandidos-publications.com/10.3892/mmr.2017.7525

Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling (Review)

• Authors: 
  • Fenggen Yan
  • Xiumei Mo
  • Junfeng Liu
  • Siqi Ye
  • Xing Zeng
  • Dacan Chen
•  
• Published online on: September 19, 2017     https://doi.org/10.3892/mmr.2017.7525
• Pages: 7175-7184
•  

42 readers on Mendeley

Abstract

The thymus is critical in establishing and maintaining the appropriate microenvironment for promoting the development and selection of T cells. The function and structure of the thymus gland has been extensively studied, particularly as the thymus serves an important physiological role in the lymphatic system. Numerous studies have investigated the morphological features of thymic involution. Recently, research attention has increasingly been focused on thymic proteins as targets for drug intervention. Omics approaches have yielded novel insights into the thymus and possible drug targets. The present review addresses the signaling and transcriptional functions of the thymus, including the molecular mechanisms underlying the regulatory functions of T cells and their role in the immune system. In addition, the levels of cytokines secreted in the thymus have a significant effect on thymic functions, including thymocyte migration and development, thymic atrophy and thymic recovery. Furthermore, the regulation and molecular mechanisms of stress‑mediated thymic atrophy and involution were investigated, with particular emphasis on thymic function as a potential target for drug development and discovery using proteomics.

요약

흉선은 

T세포의 발달과 선택을 촉진하는 적절한 미세환경을 구축하고 유지하는 데 

매우 중요합니다. 

흉선의 기능과 구조는 

특히 흉선이 림프계에서 중요한 생리학적 역할을 수행하기 때문에 

광범위하게 연구되어 왔습니다. 

수많은 연구가 흉선 퇴화의 형태학적 특징을 조사했습니다. 

최근에는 약물 개입의 대상으로서 

흉선 단백질에 대한 연구가 점점 더 집중되고 있습니다. 

오믹스 접근법은 흉선과 가능한 약물 표적에 대한 새로운 통찰력을 제공했습니다. 

본 리뷰는 

T 세포의 조절 기능과 면역 체계에서의 역할에 기초한 분자 메커니즘을 포함하여 

흉선의 신호 전달과 전사 기능을 다룹니다. 

또한, 흉선에서 분비되는 사이토카인의 수준은 

흉선세포의 이동과 발달, 

흉선 위축과 흉선 회복을 포함한 흉선 기능에 상당한 영향을 미칩니다. 

또한, 

스트레스에 의한 흉선 위축과 퇴화의 조절과 분자 기전을 조사했으며, 

특히 단백질체학을 이용한 약물 개발과 발견의 잠재적 표적으로서의 흉선 기능에 중점을 두었습니다.

Introduction

The thymus is a bilobed organ located in the superior mediastinum of the thorax, above the heart and behind the sternum. It can be divided into two main subcompartments: The cortex and the medulla. Each subcompartment contains numerous subtypes of thymic epithelial cells (TECs), in addition to dendritic cells, mesenchymal cells and endothelial cells (1–3). In addition, the thymus establishes and maintains thymic microenvironments, which are capable of supporting the efficient development of T cells. The maintenance of these microenvironments is dependent upon the specialized functions of thymic stromal cells, and other major components of the thymic microenvironment (4,5). During the development and maturation of thymocytes from bone marrow-derived T cell progenitors, three main events serve a critical role in each T cell bearing a unique T cell receptor (TCR): The rearrangement and expression‎ of TCRα and β loci, which depends on their somatic assembly; positive selection [the identification of cells that are able to recognize self-major histocompatibility complex (MHC) in antigen presentation to T cells]; and negative selection (the elimination of T cells that are potentially autoreactive). T cells that survive the selection processes eventually become mature cluster of differentiation (CD)4+ or CD8+ single positive T cells (Fig. 1). These processes ensure a population of non-autoreactive peripheral T cells. T cell migration is directed by several mediators, including chemokine receptors and G protein-coupled receptors (GPCR), which are supported by guiding stromal structures and by TECs, including cortical TECs and medullary TECs (mTEC). The TECs form a three-dimensionally oriented network, rather than the more ‘typical’ two-dimensional (2D) epithelial structures (6,7). It is important to determine the molecular mechanisms underlying the thymic regulation of T cell development and of the proteins involved in T cell recognition. However, to the best of our knowledge, the mechanisms underlying these processes have not yet been fully explored.

소개

흉선은 흉부 상부 종격동,

즉 심장 위와 흉골 뒤쪽에 위치한 양엽 기관입니다.

흉선은

크게 피질과 수질이라는 두 개의 하위 구획으로 나눌 수 있습니다.

각 하위 구획에는

수지상 세포, 중간엽 세포, 내피 세포(1-3) 외에

수많은 유형의 흉선 상피 세포(TEC)가 포함되어 있습니다.

또한,

흉선은

T세포의 효율적인 발달을 지원할 수 있는

흉선 미세환경을 형성하고 유지합니다.

이러한 미세환경의 유지는

흉선 기질 세포의 특수 기능과 흉선 미세환경의 다른 주요 구성요소(4,5)에 의존합니다.

골수 유래 T 세포 전구세포에서

흉선 세포가 발달하고 성숙하는 동안,

고유한 T 세포 수용체(TCR)를 가진 각 T 세포에서

세 가지 주요 사건이 중요한 역할을 합니다.

체세포 조립에 의존하는 TCRα 및 β 유전자좌의 재배열과 발현;

양성 선택 [T세포에 항원 제시 시 자기 주요 조직적합성 복합체(MHC)를 인식할 수 있는 세포의 식별];

그리고 음성 선택(잠재적 자가반응성 T세포의 제거). 선택 과정을 통과한 T 세포는

결국 성숙된 CD4+ 또는 CD8+ 단일 양성 T 세포 집단이 됩니다(그림 1).

이러한 과정을 통해

비자가반응성 말초 T 세포 집단이 확보됩니다.

T 세포의 이동은

여러 매개체(화학주성 수용체, G 단백질 결합 수용체(GPCR) 등)에 의해 유도되며,

이 매개체들은 안내성 기질 구조와 대뇌피질 TEC, 골수 TEC(mTEC)를 포함한 TEC에 의해 지원됩니다.

TEC은 좀 더 '전형적인' 2차원(2D) 상피 구조가 아니라 3차원적으로 배열된 네트워크를 형성합니다(6,7).

T세포 발달과 T세포 인식에 관여하는 단백질에 대한 흉선 조절의 기초가 되는 분자 메커니즘을 규명하는 것이 중요합니다.

그러나 우리가 아는 한, 이러한 과정의 기초가 되는 메커니즘은 아직 완전히 밝혀지지 않았습니다.

Figure 1.T cell development in the thymus. CD, cluster of differentiation; CMJ, corticomedullary junction; cTEC, cortical thymic epithelial cell; DN, differentiation; DP, double positive; mTEC, medullary thymic epithelial cell; SP, single positive.

Molecular mechanisms underlying regulatory T cell generation in the thymus

In 1969, Nishizuka and Sakakura were the first to present a mechanism for the generation of regulatory T (Treg) cells in the thymus, based on a neonatal thymectomy experiment (8). Treg cells in the thymus are vital for the negative regulation of immune-mediated inflammation, which features prominently in autoimmune and autoinflammatory disorders, acute allergies, cancer, chronic infections and commensal microbiota. They are also important for the regulation of metabolic inflammation for homeostasis and peripheral tolerance (9–11). Recent studies have demonstrated that mice lacking the forkhead box P3 (Foxp3) transcription factor experience overwhelming autoimmune pathology, which they succumb to in a matter of weeks (12,13). Although CD25 is not a specific marker expressed exclusively on Treg cells, using specific anti-CD25 antibodies for the depletion or inactivation of Treg cells, in combination with immunostimulation, is an attractive treatment modality, particularly in anti-tumour immunotherapy (14). The current understanding is that Treg cell development occurs when the TCR avidity for self-antigens lies between the TCR avidities that drive positive and negative selection (15–19). TCR engagement is also known to stimulate various downstream signaling molecules and transcription factors. This stimulation leads to an intricate web of downstream intracellular signaling events. Proteins important in thymic Treg cell function include phosphoinositide 3-kinase, protein kinase B (AKT), mammalian target of rapamycin (mTOR), nuclear factor of activated T cells, transcription factor activator protein 1 and nuclear factor-κB (NF-κB). Numerous pathways contribute to Treg cell development, including the TCR, AKT-mTOR and NF-κB pathways, among others (20–22). Various types of antigen-presenting cells (APCs) capture and present antigens to thymocytes through a complex network of signaling pathways (Fig. 2). In addition, calcium signaling appears to be involved in thymic Treg cell development (23). Furthermore, increased generation of the Foxp3 protein in developing thymic Treg cells may have a positive role in Ca2+ signaling (24,25). However, calcium is also a powerful negative regulator of Foxp3 in the AKT-mTOR pathway. Phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signaling regulates the phosphorylation and inhibition of forkhead box O (FoxO) transcription factors. The FoxO transcription factors have recently been reported to facilitate the expression‎ of Foxp3 and Treg cell development (26–28). Although natural Treg (nTreg) and induced Treg (iTreg) cells can enforce tolerance, iTreg cells, such as those derived from commensal bacteria in the gut, may have a particularly important role as they increase antigen receptor diversity (29,30). The mechanisms underlying the development and antigen specificities of nTreg and iTreg cells are likely to differ.

흉선에서 조절 T세포가 생성되는 분자 메커니즘

1969년, 니시즈카와 사카쿠라는

신생아 흉선 절제술을 기반으로 한 실험(8)을 통해

흉선에서 조절 T세포(Treg)가 생성되는 메커니즘을 최초로 제시했습니다.

흉선 내의 조절 T세포는

자가면역 및 자가염증성 질환, 급성 알레르기, 암, 만성 감염,

공생 미생물군집에서 두드러지게 나타나는

면역 매개 염증의  조절에 필수적입니다.

또한,

그들은 항상성 및 말초 내성을 위한

대사성 염증의 조절에도 중요합니다(9-11).

최근 연구에 따르면 포크헤드 박스 P3(Foxp3) 전사 인자가 결핍된 생쥐는

압도적인 자가면역 병리학을 경험하고,

몇 주 만에 사망에 이르게 됩니다(12,13).

CD25가 Treg 세포에서만 발현되는 특정 표지자는 아니지만,

Treg 세포의 고갈 또는 비활성화에 특이적인 항-CD25 항체를 사용하고

면역 자극을 병행하는 것은 특히 항암 면역 요법에서 매력적인 치료 방법입니다(14).

현재의 이해에 따르면,

자가 항원에 대한 TCR 친화성이 양성 및 음성 선택을 유도하는 TCR 친화성 사이에 위치할 때,

Treg 세포가 발달합니다(15-19).

TCR의 관여는

다양한 다운스트림 신호 전달 분자와 전사 인자를 자극하는 것으로 알려져 있습니다.

이러한 자극은 복잡한 다운스트림 세포 내 신호 전달 사건의 망을 형성합니다.

흉선 Treg 세포 기능에 중요한 단백질에는

포스포이노시타이드 3-키나제,

단백질 키나아제 B(AKT),

포유류 표적 라파마이신(mTOR),

활성화된 T 세포의 핵 인자, 전사 인자 활성화 단백질 1, 핵 인자-κB(NF-κB) 등이 있습니다.

TCR, AKT-mTOR, NF-κB 경로 등 수많은 경로가

Treg 세포 발달에 기여합니다(20-22).

다양한 유형의 항원 제시 세포(antigen-presenting cells, APC)가

복잡한 신호 전달 경로를 통해 항원을 포획하여

흉선세포에 제시합니다(그림 2).

또한,

칼슘 신호 전달은 흉선에서

T-reg 세포의 발달에 관여하는 것으로 보입니다(23).

또한,

흉선에서 T-reg 세포가 발달하는 과정에서 Foxp3 단백질의 생성량이 증가하면

Ca2+ 신호 전달에 긍정적인 역할을 할 수 있습니다(24,25).

그러나

칼슘은 AKT-mTOR 경로에서 Foxp3의 강력한 부정적 조절자이기도 합니다.

포스파티딜이노시톨-4,5-비스포스페이트 3-키나제/AKT 신호는

포크헤드 박스 O(FoxO) 전사 인자의 인산화 및 억제를 조절합니다.

FoxO 전사 인자는 최근 Foxp3의 발현과 조절 T세포 발달을 촉진하는 것으로 보고되었습니다(26-28). 자연 조절 T세포(nTreg)와 유도 조절 T세포(iTreg) 모두 관용을 촉진할 수 있지만, 장내 공생 박테리아에서 유래된 iTreg 세포는 항원 수용체의 다양성을 증가시키기 때문에 특히 중요한 역할을 할 수 있습니다(29,30). nTreg와 iTreg 세포의 발달과 항원 특이성의 기저에 있는 메커니즘은 다를 가능성이 큽니다.

Figure 2.Molecular mechanisms underlying the generation of thymic regulatory T cells. Molecular signals downstream of the TCR are presented. AP, activator protein; APC, antigen-presenting cell; BCL, B cell lymphoma; BTLA, B and T lymphocyte attenuator; Ca, calcium; CARMA, CARD-containing MAGUK protein; CD, cluster of differentiation; DAG, diacylglycerol; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; IKKβ, inhibitor of nuclear factor κB; ITIM, immunoreceptor tyrosine-based inhibition motif; MEK, mitogen-activated extracellular signal-regulated kinase; MHC, major histocompatibility complex; FoxO, forkhead box protein O; FOXP3, forkhead box protein 3; NFAT, nuclear factor of activated T; Grb, growth factor receptor-bound protein; LAT, linker for activation of T cells; LCK, lymphocyte-specific protein tyrosine kinase p56; MALT, mucosa-associated lymphoid tissue lymphoma translocation protein; mTOR, mechanistic target of rapamycin; NF, nuclear factor; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PK, protein kinase; PL, phospholipase; PTP, protein-tyrosine phosphatase; Ras, rat sarcoma also known as p21; Raf, rapidly accelerated fibrosarcoma; SHP, SH2-containing protein tyrosine phosphatase; SOS, Son of Sevenless; STIM, stromal interaction molecule; TAK, transforming growth factor beta-activated kinase; ZAP70, ζ-associated protein of 70 kD.

Over the past few years, substantial progress has been made in understanding the developmental process of thymic Treg cells and the molecular mechanism underlying their regulation in the thymus. However, there remain numerous unanswered questions. For example, the molecular differences between immature CD4+ single positive (SP) thymocytes in the thymus and naive peripheral T cells remain unknown. In addition, it remains to be elucidated why Foxp3 expression‎ occurs predominantly in CD4+, and not CD8+, SP thymocytes, The present review aimed to understand these molecular mechanisms and how these molecular components are ‘wired’ into regulatory signaling and transcriptional networks. Achieving this may aid in the improvement of therapeutic strategies used to treat autoimmune and inflammatory disorders.

지난 몇 년 동안, 흉선에서 조절되는 흉선 T세포 조절 세포의 발달 과정과 그 조절의 기초가 되는 분자 메커니즘을 이해하는 데 상당한 진전이 있었습니다. 그러나, 아직 답이 없는 질문이 많이 남아 있습니다. 예를 들어, 흉선에서 미성숙 CD4+ 단일 양성(SP) 흉선 세포와 순혈 말초 T세포 사이의 분자 차이는 아직 밝혀지지 않았습니다. 또한, 왜 Foxp3 발현이 CD8+가 아닌 CD4+의 SP 흉선 세포에서 주로 발생하는지 밝혀지지 않았습니다. 본 연구의 목적은 이러한 분자 메커니즘과 이러한 분자 구성 요소가 어떻게 조절 신호 및 전사 네트워크에 '연결'되는지를 이해하는 것이었습니다. 이를 달성하면 자가면역 및 염증성 질환을 치료하는 데 사용되는 치료 전략의 개선에 도움이 될 수 있습니다.

Effects of cytokines on thymic function

Cytokines serve as molecular messengers between immune cells, and have been reported to be of major importance to thymic function. The effects of cytokine cascades on thymic function are generally well understood. Almost all types of thymic cells can produce cytokines, either spontaneously or following stimulation with stimulating agents, including lipopolysaccharides, phytohemagglutinin and ionomycin. The most important of the thymic cell subsets are TECs, which are the principal source of cytokines and chemokines required in early T cell development (31). The differential expression‎ of major cytokines produced by TECs can be divided into four branches: Hemopoietins, proinflammatory cytokines, suppressor cytokines and interleukin (IL)-6 and IL-7 cytokines (32,33). Notably, cytokines and other growth factors serve important roles in thymic function, regulating various cellular processes. However, the functions of numerous cytokines in the thymus are not well understood. Understanding the effects of intrathymic cytokines may reveal some unknown aspects of thymic physiology.

The thymus produces hormones and cytokines that regulate immune function. A previous study identified at least six types of thymic cells (34). The histological features of the thymus are broadly divided into the central medulla and a peripheral cortex. Previous research has demonstrated that cytokine secretion by T lymphocytes has a vital role in mounting adaptive immune responses (35). In addition, the large number of cytokines produced by the thymus maintains a fine balance between thymocyte proliferation, maturation, activation, differentiation and survival inhibition. Thymic cells also secrete the peptides IL-1, IL-3, IL-4 and IL-6, and three major thymic hormones, thymosins, thymopoietin and thymulin (36–39). Thymic hormones serve a major role in preserving the functions of the immune system, and cytokines have essential roles in the control of immune responses.

Cytokines are small polypeptides that regulate cell function and are predominantly secreted by immune cells. Numerous cytokines responsible for the modulation of T cell differentiation are produced by thymocytes and TECs. The ability of thymocytes to produce cytokines is important in the regulation of thymic cytokine production and the responses to their action (Fig. 3). Of these regulators, IL-7 serves a particular role in thymocyte differentiation; IL-7 has been reported to promote the rearrangement of TCR genes by enhancing the production and activity of recombinases (40,41). The thymic production of Treg cells requires IL-2, which is also required during T cell development in the thymus and for the maturation of Treg cells. Recent studies have reported that IL-2 receptor is functionally active within the thymus; it increases the number of CD4+Foxp3+ thymocytes and the expression‎ of Foxp3 and CD25 to normal levels (42–44). IL-4 is another cytokine produced by T cells whose receptor contains a γ(c)-chain. It has previously been demonstrated that IL-4 is synergistic with IL-2 in the induction of thymocyte proliferation in fetal thymic organ culture. In addition, IL-4 supports thymocytes through successive phases of proliferation, acting alongside stimulatory agents (45,46). Recently, research has been directed at the cytokine IL-10, which is produced by Treg cells, and other chronically stimulated T helper cells, B cells and APCs. IL-10 is important for maintaining immune homeostasis at mucosal surfaces and also contributes to immune suppression (47–49).

사이토카인이 흉선 기능에 미치는 영향

사이토카인은

면역세포들 사이의 분자 메신저 역할을 하며,

흉선 기능에 매우 중요한 것으로 알려져 있습니다.

사이토카인 캐스케이드가 흉선 기능에 미치는 영향은 일반적으로 잘 알려져 있습니다.

거의 모든 유형의 흉선 세포는

자발적으로 또는 리포폴리사카라이드, 피토헤마글루티닌, 이오노마이신 등의 자극제를 통해

자극을 받은 후 사이토카인을 생성할 수 있습니다.

흉선 세포 하위 집합체 중 가장 중요한 것은 TEC로,

초기 T 세포 발달에 필요한 사이토카인과 케모카인의 주요 공급원입니다(31).

TEC에 의해 생성되는 주요 사이토카인의 차등 발현은 네 가지로 나눌 수 있습니다.

조혈인자, 전염증성 사이토카인, 억제성 사이토카인, 인터루킨(IL)-6 및 IL-7 사이토카인(32,33).

특히,

사이토카인과 기타 성장 인자는

다양한 세포 과정을 조절하는 흉선 기능에 중요한 역할을 합니다.

그러나,

흉선에서 수많은 사이토카인의 기능은 잘 알려져 있지 않습니다.

흉선 내 사이토카인의 효과를 이해하면 흉선 생리학에 대해 알려지지 않은 측면을 밝혀낼 수 있습니다.

흉선은

면역 기능을 조절하는 호르몬과 사이토카인을 생성합니다.

이전 연구에 따르면, 최소 6가지 유형의 흉선 세포가 존재하는 것으로 밝혀졌습니다(34).

흉선의 조직학적 특징은 크게 중심 수질과 주변 피질로 나뉩니다.

이전 연구에 따르면,

T 림프구에 의한 사이토카인 분비가

적응성 면역 반응을 강화하는 데 중요한 역할을 한다는 사실이 밝혀졌습니다(35).

또한,

흉선에서 생성되는 많은 수의 사이토카인은

흉선세포의 증식, 성숙, 활성화, 분화, 생존 억제 사이의 미세한 균형을 유지합니다.

흉선세포는

또한 펩타이드 IL-1, IL-3, IL-4, IL-6와

세 가지 주요 흉선 호르몬인 티모신, 티모포이에틴, 티뮬린을 분비합니다(36-39).

흉선 호르몬은

면역체계의 기능을 유지하는 데 중요한 역할을 하며,

사이토카인은 면역반응을 조절하는 데 필수적인 역할을 합니다.

사이토카인은

세포 기능을 조절하는 작은 폴리펩티드로, 주로 면역세포에 의해 분비됩니다.

T세포 분화를 조절하는 수많은 사이토카인은

흉선세포와 TEC에 의해 생성됩니다.

사이토카인을 생산하는 흉선세포의 능력은

흉선 사이토카인 생산과 그 작용에 대한 반응의 조절에 중요합니다(그림 3).

이러한 조절자 중 IL-7은

흉선세포 분화에 특별한 역할을 합니다.

IL-7은 재조합효소의 생산과 활성을 강화하여

TCR 유전자의 재배열을 촉진하는 것으로 보고되었습니다(40,41).

Treg 세포의 흉선 생산에는 IL-2가 필요하며,

이는 또한 흉선에서의 T 세포 발달과 Treg 세포의 성숙에도 필요합니다.

최근 연구에 따르면,

IL-2 수용체는

흉선 내에서 기능적으로 활성화되어

CD4+Foxp3+ 흉선 세포의 수와 Foxp3 및 CD25의 발현을 정상 수준으로 증가시킵니다(42-44).

IL-4는 γ(c)-사슬을 포함하는 수용체를 가진 T세포에 의해 생성되는 또 다른 사이토카인입니다.

태아 흉선 기관 배양에서 IL-4가 IL-2와 함께 흉선세포 증식을 유도하는 데 시너지 효과가 있다는 것이 이전에 입증되었습니다.

또한,

IL-4는 자극제(45,46)와 함께 작용하여 연속적인 증식 단계를 통해 흉선세포를 지원합니다.

최근에는 Treg 세포와 다른 만성 자극 T 헬퍼 세포, B 세포,

그리고 APC에 의해 생성되는 사이토카인 IL-10에 대한 연구가 진행되고 있습니다.

IL-10은

점막 표면의 면역 항상성을 유지하는 데 중요하며,

면역 억제에 기여합니다(47-49).

Figure 3.Role of cytokines in T cell development. CD, cluster of differentiation; DN, double negative; DP, double positive; IL, interleukin; Treg, regulatory T cell.

Interferon (IFN)-γ has numerous effects on TECs; it activates TECs and increases surface expression‎ of MHC classes I and II, and other membrane proteins (50). Furthermore, IFN-γ stimulates the secretion of IL-6 by TECs (51). IFN-γ also supports thymocyte differentiation, through its action on TEC functions. Tumor necrosis factor (TNF)-α has been reported to have an important role in the regulation of thymocyte production, inducing apoptosis and the proliferation of immature CD3−CD4−CD8− T cells in the presence of IL-7 (52). Furthermore, TNF-α and IL-1 participate as cofactors in the induction of CD4−CD8− thymocyte commitment and differentiation (53). TNF-α also stimulates the production of IL-6 and enhances the apoptosis of CD4+CD8+ cells induced by glucocorticoids (54,55).

Some molecules are multifunctional and serve different functions in the cytokine system within the thymus than they do in peripheral compartments of the immune system. For example, some cytokines are pleiotropic in their biological activities and exhibit different roles in these different systems. The principal roles of thymic cytokines are in constitutive processes, including thymocyte migration and development, and the mediation of cell populations, but not inducible ones, such as immune response/tolerance or inflammation, as in the periphery. The synthesis of cytokines and the expression‎ of their receptors in the thymus is usually spontaneous, or is induced by cell-cell interactions, unlike in the periphery. Information regarding the production of cytokines in the thymus and the biological activity of these cytokines is summarized in Table I.

인터페론(IFN)-γ는 TECs에 다양한 영향을 미칩니다.

TECs를 활성화시키고 MHC 클래스 I과 II, 그리고 다른 막 단백질(50개)의 표면 발현을 증가시킵니다.

또한, IFN-γ는 TEC에 의한 IL-6 분비를 촉진합니다(51). IFN-γ는 TEC 기능에 작용함으로써 흉선세포 분화를 지원합니다. 종양 괴사 인자(TNF)-α는 IL-7의 존재 하에서 미성숙 CD3-CD4-CD8- T 세포의 세포 사멸과 증식을 유도함으로써 흉선세포 생산 조절에 중요한 역할을 하는 것으로 보고되었습니다(52). 또한, TNF-α와 IL-1은 CD4-CD8- 흉선세포의 확립과 분화 유도에서 보조 인자로 작용합니다(53). TNF-α는 또한 IL-6의 생성을 촉진하고 글루코코르티코이드에 의해 유도된 CD4+CD8+ 세포의 세포자멸사를 강화합니다(54,55).

일부 분자는 다기능적이며, 흉선 내 사이토카인 시스템에서 면역계의 말초 구획에서와 다른 기능을 수행합니다. 예를 들어, 일부 사이토카인은 생물학적 활동에서 다기능적이며, 이러한 다른 시스템에서 다른 역할을 수행합니다. 흉선 사이토카인의 주요 역할은 흉선 세포의 이동과 발달, 그리고 세포 집단의 중재를 포함하는 구성적 과정에 있지만, 말초에서와 같이 면역 반응/내성 또는 염증과 같은 유도 가능한 과정에는 해당하지 않습니다. 사이토카인의 합성과 흉선에서의 수용체의 발현은 주변 조직과는 달리, 보통 자발적으로 일어나거나 세포-세포 상호작용에 의해 유도됩니다. 흉선에서의 사이토카인 생산과 이 사이토카인의 생물학적 활동에 관한 정보는 표 I에 요약되어 있습니다.

Table I.Biological activity of cytokines affects T cell-associated thymic function.

Regulation of molecular mechanisms in stress-mediated thymic atrophy and involution

Stress is able to disrupt homeostasis of the immune system, and various stressful conditions cause acute thymic involution, including emotional distress, malnutrition and pregnancy (56,57). Furthermore, numerous processes can trigger thymic involution during pathological conditions, such as bacterial and viral infections, inflammation, disease, clinical cancer treatment and preparative regimens for bone marrow transplants (58), as presented in Fig. 4. Therefore, mechanisms must exist to regulate these processes in various contexts. It is well known that the thymus serves an important role in the body's immune response. It provides the microenvironment essential for the development of T cells from hematopoietic stem cells. The central functions of the thymus are critical to immune tolerance in several rodent and large animal models under normal or pathological conditions. These functions act through various mechanisms, such as clonal deletion or clonal anergy of self-reactive T cells, elimination or control of self-reactive T cells, and anergy of self-reactive T cells (59–63). Recent mechanistic studies regarding central and peripheral T cell tolerance have assisted in the design of novel, immunomodulating therapeutic strategies for the treatment of autoimmune diseases, and improve the prevention, detection and treatment of cancer and associated diseases, as well as exert immunoregulatory effects in transplantation outcomes using pharmacological or biological interventions (64–66). Immunosenescence and immune atrophy, which are associated with reduced immunity, are complex processes that have yet to be fully understood. Numerous factors exert a negative effect on thymopoiesis, acute stress-induced thymic atrophy and on chronic thymic involution associated with aging. These factors include starvation, environmental stressors, bacterial infection, and irradiation or immunosuppressive therapies (67–70).

스트레스에 의한 흉선 위축과 퇴화에 대한 분자 메커니즘의 조절

스트레스는 면역 체계의 항상성을 방해할 수 있으며,

정서적 고통, 영양실조, 임신 등 다양한 스트레스 조건이

급성 흉선 퇴화를 유발합니다(56,57).

또한, 그림 4에 나타난 바와 같이,

세균 및 바이러스 감염, 염증, 질병, 임상 암 치료, 골수 이식 준비 요법(58)과 같은 병리학적 조건에서

수많은 과정이 흉선 퇴화를 유발할 수 있습니다.

따라서 다양한 맥락에서 이러한 과정을 조절하는 메커니즘이 존재해야 합니다.

흉선이 신체의 면역 반응에 중요한 역할을 한다는 것은 잘 알려진 사실입니다.

그것은 조혈모세포에서 T세포가 발달하는 데 필수적인 미세환경을 제공합니다.

흉선의 중심 기능은 정상 또는 병리학적 조건 하에서 여러 설치류 및 대형 동물 모델에서 면역 관용에 매우 중요합니다.

이러한 기능은

자가반응성 T세포의 클론 삭제 또는 클론 무력화,

자가반응성 T세포의 제거 또는 통제,

자가반응성 T세포의 무력화 등 다양한 메커니즘을 통해 작용합니다(59-63).

중앙 및 주변 T 세포 내성에 관한 최근의 메커니즘 연구는

자가면역질환의 치료를 위한

새로운 면역조절 치료전략의 설계에 도움을 주었으며,

암과 관련 질병의 예방, 탐지, 치료 개선에 기여하고,

약리학적 또는 생물학적 개입을 이용한 이식 결과의 면역조절 효과를 발휘합니다(64-66).

면역력 저하와 관련된 면역노화(Immunosenescence)와 면역위축(immune atrophy)은

아직 완전히 이해되지 않은 복잡한 과정입니다.

수많은 요인들이 흉선형성,

급성 스트레스에 의한 흉선 위축,

그리고 노화와 관련된 만성 흉선 퇴화에 부정적인 영향을 미칩니다.

이러한 요인에는 기아, 환경 스트레스 요인, 세균 감염, 방사선 조사 또는 면역 억제 요법 등이 포함됩니다(67-70).

Figure 4.Model of stress-induced thymic atrophy, and thymosuppressive and thymostimulatory mediators. AIDS, acquired immunodeficiency syndrome; Cyc, cyclophosphamide; Dex, dexamethasone; Dox, doxorubicin; HIV, human immunodeficiency virus; hGH, human growth hormone; IL, interleukin; KGF, keratinocyte growth factor; TGF-β, transforming growth factor-β; TSLP, thymic stromal lymphopoietin.

The shrinkage of the thymus was reported >80 years ago by Boyd (71); however, the underlying mechanisms are not well understood. Immunosenescence is defined as deterioration in the immune system, which is associated with aging (72–74), and has attracted increasing interest in the scientific and health-care sectors alike. Thymic atrophy has often been observed due to the direct or indirect influences of drugs or the environment on the thymus. However, one other major consideration in thymic atrophy is a systemic rise in glucocorticoids and inflammatory cytokines. Unfortunately, the thymus is acutely sensitive to various stresses and injuries; therefore, it is often considered as a ‘barometer of stress’ for the body. Prolonged thymic atrophy in stress situations can contribute to peripheral T cell deficiency or can inhibit immune reconstitution, thus resulting in a decrease in thymopoiesis (75,76). Therefore, mechanistic studies have increasingly focused on thymic atrophy. A commonly used mouse model of endotoxemia-induced acute thymic atrophy has been used to reveal the effects of acute stress on thymopoiesis. For example, in a lipopolysaccharide (LPS)-induced acute thymic atrophy model, microarray analysis revealed >11,000 probe sets with significant alterations (>1.4-fold), 1 day after an LPS challenge. This finding has important implications regarding how the direct intrathymic response to an endotoxin challenge contributes to thymic involution during endotoxemia (77). In endotoxin-stressed mice, it has previously been reported that leptin administration augments thymopoiesis in LPS-treated leptin-deficient (ob/ob) mice, but not in normal mice (78). Furthermore, a recent study indicated that the number of thymocytes and TECs was significantly decreased in LPS-treated neonatal thymic involution (79).

Age-associated thymic involution must also be considered. Aging is accompanied by a decline in the function and development of the immune system. Understanding the aging process, and how that process can be delayed or reversed, may allow us to take action to adopt healthier lifestyles and live longer. Age-associated thymic involution is characterized by progressive diminution of novel T cell production (80). However, many previous findings are contradictory. Some studies have reported the effects of aging on the function of neutrophils, macrophages and natural killer cells, whereas other studies have reported no association (81,82). In addition, some studies have demonstrated that the systemic administration of keratinocyte growth factor (KGF) enhances T cell lymphopoiesis by stimulating TECs to secrete various cytokines that then act on developing thymocytes in young and old mice (83,84). Furthermore, a previous study was conducted on C57BL/6×DBA/2 recombinant inbred strains of mice to identify the genetic loci influencing age-associared thymic involution, and demonstrated that the strongest quantitative trait loci influencing the rate of thymic involution in the recombinant-inbred mice were mapped to chromosome (Chr) 9 (D9Mit20 at 62 cM) and Chr 10 (D10Mit61 at 32 cM) (85).

It is well known that stress on the immune system leads to the suppression of immune cell functions, such as in T cells, macrophages, dendritic cells and B cells, and the atrophy of immune organs, predominantly the thymus and spleen. The thymus is one of the central organs of the immune system, and is essential for the development of the adaptive immune system. Insult, infection, dysregulation of positive and negative selection, suppression of cell adhesion, chemotaxis, cytotoxicity, increased apoptosis or antigen presentation in the thymus, may all lead to autoimmunity or immunosuppression (86,87). Previous studies have suggested that exposure to immunosuppressive agents, such as diethylstilbestrol, dexamethasone (DEX), azathioprine, cyclophosphamide (Cyc), 2,3,7,8-tetrachlorodibenzo-p-dioxin or cyclosporin A may induce immunotoxic effects resulting in hypocellularity, apoptosis and atrophy in the thymus (88–92). This provides evidence regarding the molecular mechanisms and cellular targets involved in thymic atrophy-induced immunosuppression. DEX is a synthetic glucocorticoid compound with potent anti-inflammatory activity, which is associated with clinically significant side effects that severely limit its therapeutic use. In a previous study, DEX (20 mg/kg) was administered to C57Bl/6 mice via intraperitoneal injection; the thymuses were then harvested 5 days after treatment. Analysis of the thymic tissues detected a depletion of CD4+CD8+ double positive thymocytes, and upregulation of IL-22 and IL-23 in wild-type mice (93). In another study, the immunosuppressant cyclosporin A was reported to induce extensive reductions in the autoimmune regulator tolerance-inducing MHC class IIhigh mTECs (mTEChigh). The most distinctive effects of Cyc and DEX exposure were extensive reductions in thymocytes and stromal cells, and, as with cyclosporin A, severely depleted tolerance-inducing mTEChigh (91).

흉선의 위축은 80년 전 Boyd(71)에 의해 보고되었지만,

그 근본적인 메커니즘은 잘 알려져 있지 않습니다.

면역노화(immunosenescence)는

노화와 관련된 면역체계의 악화로 정의되며(72-74),

과학 및 의료 분야에서 점점 더 많은 관심을 받고 있습니다.

흉선 위축은

약물이나 환경이 흉선에 직접적 또는 간접적으로 영향을 미치기 때문에 자주 관찰됩니다.

그러나,

흉선 위축의 또 다른 주요 원인은

전신적인 글루코코르티코이드와

염증성 사이토카인의 증가입니다.

불행히도,

흉선은 다양한 스트레스와 부상에 매우 민감하기 때문에,

종종 신체의 '스트레스 지표'로 간주됩니다.

스트레스 상황에서 장기간 흉선 위축이 발생하면 말초 T 세포 결핍에 기여하거나 면역 재구성을 억제하여 흉선 조성에 영향을 미칠 수 있습니다(75,76). 따라서, 기계론적 연구는 점점 더 흉선 위축에 초점을 맞추고 있습니다. 급성 스트레스가 흉선 생성에 미치는 영향을 밝히기 위해, 일반적으로 사용되는 엔도톡신혈증 유발 급성 흉선 위축 마우스 모델이 사용되었습니다. 예를 들어, 리포폴리사카라이드(LPS) 유발 급성 흉선 위축 모델에서, 마이크로어레이 분석 결과, LPS 투여 1일 후, 유의미한 변화(1.4배 이상)를 보이는 11,000개 이상의 프로브 세트가 발견되었습니다. 이 발견은 내독소 자극에 대한 직접적인 흉선 내 반응이 내독소 혈증 동안 흉선 퇴화에 어떻게 기여하는지에 대한 중요한 시사점을 제공합니다(77). 내독소에 스트레스를 받은 생쥐에서, 렙틴 투여가 LPS로 처리된 렙틴 결핍(ob/ob) 생쥐의 흉선 생성을 증가시키는 것으로 보고되었지만, 정상 생쥐에서는 그렇지 않았습니다(78). 또한, 최근의 연구에 따르면 LPS로 처리된 신생아 흉선 퇴화에서 흉선세포와 TEC의 수가 현저하게 감소하는 것으로 나타났습니다(79).

나이 관련 흉선 위축도 고려해야 합니다. 노화는 면역체계의 기능과 발달의 감소를 동반합니다. 노화 과정을 이해하고, 그 과정을 지연시키거나 되돌릴 수 있는 방법을 이해하면, 더 건강한 생활 방식을 채택하고 더 오래 살 수 있도록 조치를 취할 수 있습니다. 나이 관련 흉선 위축은 새로운 T 세포 생산의 점진적인 감소를 특징으로 합니다(80). 그러나, 많은 이전의 연구 결과는 모순적입니다. 일부 연구에서는 호중구, 대식세포, 자연살해세포의 기능에 대한 노화의 영향을 보고한 반면, 다른 연구에서는 연관성이 없다고 보고했습니다(81,82). 또한 일부 연구에서는 각질세포 성장 인자(KGF)의 전신 투여가 TEC를 자극하여 다양한 사이토카인을 분비하게 하고, 이 사이토카인이 젊고 늙은 생쥐의 발달 중인 흉선세포에 작용함으로써 T 세포 림프구 생성을 향상시킨다는 것을 입증했습니다(83,84). 또한, C57BL/6×DBA/2 재조합 근친 마우스 계통에 대한 이전 연구에서는 연령과 관련된 흉선 퇴화에 영향을 미치는 유전적 위치를 확인하기 위해, 흉선 퇴화 속도에 영향을 미치는 가장 강력한 정량적 형질좌위가 퇴화에 영향을 미치는 가장 강력한 양적 형질좌위가 염색체 9번(62cM의 D9Mit20)과 10번(32cM의 D10Mit61)에 매핑되었다는 것을 증명했습니다(85).

면역계에 스트레스가 가해지면 T세포, 대식세포, 수지상세포, B세포와 같은 면역세포의 기능이 억제되고, 주로 흉선과 비장을 비롯한 면역 기관이 위축된다는 것은 잘 알려진 사실입니다. 흉선은 면역계의 중심 기관 중 하나이며, 적응성 면역계의 발달에 필수적인 기관입니다. 면역체계의 자극, 감염, 양성 및 음성 선택의 조절 장애, 세포 부착 억제, 화학주성, 세포 독성, 흉선에서의 세포 사멸 또는 항원 제시 증가 등은 모두 자가면역 또는 면역억제로 이어질 수 있습니다(86,87). 이전 연구에 따르면, 디에틸스틸베스트롤, 덱사메타손(DEX), 아자티오프린, 사이클로포스파미드(Cyc), 2,3,7,8-테트라클로로디벤조-p-다이옥신 또는 사이클로스포린 A와 같은 면역억제제에 노출되면 면역독성 효과를 유발하여 흉선의 세포 감소, 세포자멸사 및 위축을 초래할 수 있습니다(88-92). 이것은 흉선 위축으로 인한 면역 억제에 관여하는 분자 메커니즘과 세포 표적에 관한 증거를 제공합니다. DEX는 강력한 항염증 작용을 하는 합성 글루코코르티코이드 화합물로, 임상적으로 유의미한 부작용과 관련되어 있어 치료적 사용을 심각하게 제한합니다. 이전 연구에서 DEX(20mg/kg)를 복강 내 주사를 통해 C57Bl/6 마우스에게 투여한 후, 치료 5일 후에 흉선을 채취했습니다. 흉선 조직 분석 결과, CD4+CD8+ 이중 양성 흉선 세포가 감소하고, 야생형 마우스에서 IL-22와 IL-23의 발현이 증가하는 것으로 나타났습니다(93). 또 다른 연구에서는 면역 억제제인 사이클로스포린 A가 자가면역 조절기 내성 유도 MHC 클래스 IIhigh mTEC(mTEChigh)를 광범위하게 감소시키는 것으로 보고되었습니다. 사이클로포스포린과 DEX 노출의 가장 두드러진 효과는 흉선세포와 기질세포의 광범위한 감소였으며, 사이클로포스포린 A와 마찬가지로 내성 유도 mTEChigh(91)가 심각하게 고갈되었습니다.

Prediction of potential drug targets on the thymus using proteomics

The thymus remains still largely uncharted territory that invites further investigation. Understanding the role of the thymus in T cell generation and homeostasis, and understanding exactly how such systems work and what proteins are involved has resulted in greater interest in thymus organogenesis. The application of systems biology, combined with more traditional methods, is essential to uncover and optimize the molecular mechanisms underlying effects (drug-induced or otherwise) on the thymus. These methods will allow the study of novel aspects of thymic function and aid understanding regarding thymic function, morphogenesis and development. This knowledge may then be used to identify potential drug targets. In addition, these methods will prove useful not only for studying gene and protein function in thymus organogenesis, but also for clarifying the origin and lineage relationship between cortical and medullary epithelial cell types. Recently, modern approaches to chemical genomics, metabolomics, genomics, transcriptomics, pharmacogenomics, microbiomics and proteomics have proved to be useful in the identification and characterization of molecular mechanisms underlying all aspects of pharmacological sciences and physiological processes, and in other areas (94,95). Therefore, evidence suggests that proteomics may be effectively used in the in-depth study of the thymus in different models and pathological conditions.

Proteomics is the large-scale study of proteins, and facilitates the systematic analysis of protein molecules in complicated biological systems. Turiák et al (96) focused on the proteomic characterization of thymocyte-derived microvesicles (MVs) and apoptotic bodies in BALB/c mice; 195 and 142 proteins were identified in MVs and apoptotic bodies, respectively. This previous study also identified numerous molecules known to serve important roles in the immune system, such as MHCI, MHCII, CD5 and CD97 in MVs, and CD45 in both types of vesicles. Similarly, Billing et al (97) used proteomic profiling analysis to measure the non-genomic and concomitant genomic effects of acute restraint stress on rat thymocytes. In recent years, several methods have been developed for relative and absolute quantitative proteomics. The most widely used quantitative techniques include gel-based [2D gel electrophoresis, difference gel electrophoresis (DIGE)] and liquid chromatography-mass spectrometry (MS)-based methods (isotope-coded affinity tag, stable isotope labeling with amino acids in cell culture, isobaric tags for relative and absolute quantitation). MS-based proteomics methods are typically divided into two categories: Label-free or label-based approaches (98). Proteomics research is applied to a wide range of biological systems for the study of differentially expressed proteins, particularly candidates for biomarker discovery and validation, understanding disease processes and clinical proteomics (99). Notably, in a previous study quantitative 2D-DIGE with matrix-assisted laser desorption/ionization-time of flight (TOF)/TOF MS was used to identify 108 proteins with differential subcellular localizations in rat thymocytes; this may be the first study to determine the rapid effects of stress-induced hypothalamus-pituitary-adrenal activation at the proteome level in vivo (97). According to our current understanding, doxorubicin (DOX) treatment leads to degeneration of the thymus. Proteomics analysis is consistent with the notion that DOX treatment in vivo leads to thymic senescence (100). Cyc has also been reported to induce immunosuppression and thymic atrophy. Proteomic analysis indicated that possible target-related processing was instigated following Cyc-treatment in mice (101). Apoptosis serves an essential role in the development and maturation of T lymphocytes during mammalian thymus maturation. Experiments have indicated that several proteins were differentially regulated in the cytosol of T cell precursors by a signal from TCR, as identified using proteomic techniques (102). Proteomics has been widely used to study the experimentally induced acute phase reaction, and to study numerous disease models associated with cancer and inflammatory diseases (103,104). A previous study revealed the cellular and molecular mechanisms using proteomic approaches combined with bioinformatics analysis (105). Despite the increased use of proteomics, knowledge of protein interactions and pathway networks remains largely incomplete; however, data generated by quantitative proteomics can still provide valuable insights (106).

Final remarks

More than 50 years ago, Miller (107) conducted seminal studies on the immunological function of the thymus using neonatally thymectomized mice. The importance of this primary lymphoid organ was quickly established, as the thymus provides a unique microenvironment in which T cells or T lymphocytes undergo development, differentiation and clonal expansion during the physiological development of the immune system. In recent years, there has been a marked interest in the association between the immune system and the thymus, generating results that confirmed that the thymus was endowed with an immune function. The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. It appears that Treg cell-mediated suppression serves as a vital mechanism in the negative regulation of immune-mediated inflammation, and features prominently in autoimmune and autoinflammatory disorders, and pathologies induced by fungi, parasites, allergies, acute and chronic infections, cancer and metabolic inflammation. Treg cells are considered important to researchers in their efforts to increase the efficacy of vaccines for cancer, acquired immune deficiency syndrome and autoimmune diseases. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage has facilitated recent progress in understanding the biology of Treg cells. These findings may provide novel targets for subsequent drug development.

There is an increasingly in-depth understanding of cytokines and their activities in biological pathways. Therefore, an improved understanding regarding the cytokine network is essential to determine the role of numerous key cytokines, and to modulate thymic function. Cytokines, such as ILs, may be useful in improving the functionality of the thymus and may be used to treat immunodeficiency or autoimmune diseases. It has been reported that cytokines, including IL-6, IL-7 receptor, IL-10 and IL-22, serve a key regulatory role in T cell growth and differentiation processes in the thymus. These cytokines may be mediated through various regulatory mechanisms and signaling pathways to establish a protective effect on the thymus. Understanding these pathways will increase the understanding of the regulatory mechanism of the thymus and the biology of Treg cells and secreted cytokine function. Previous studies have analyzed the effects of cytokine therapy as a complementary schedule to conventional therapy with γ-globulin (108–110). The results suggested that the treatment has a long-term positive effect on the immune response, relative to other therapeutic interventions. A combination of IFN-α2b, thymic factors, γ-globulin and granulocyte-macrophage colony-stimulating factor may be a promising to treat common variable immunodeficiency. In addition, a previous study reported that cytokines not only serve an essential role during early T cell development, but are also responsible for the development of other thymic cells, such as thymic dendritic cells, generated from precursors produced in bone marrow (32). At present, information on this topic is limited. An essential difference between cytokine production inside the thymus and in peripheral organs is the different levels of dependence on cell activation, and possibly cross talk, depending on the cytokine environment and situation.

Studying protective mechanisms may provide novel directions in research and the development of drugs for the treatment of various stresses to the thymus, including immunosenescence, immune atrophy and immunosuppression. There have been reports of several small molecules having a protective effect on the thymus, including leptin, KGF and IL-22. Studies have also explored the molecular mechanisms involved, predominantly using mice (70,111). In various chemical stress and thymic atrophy models, these active molecules can enhance the remodeling of the thymus, protecting the thymus from some stressors, such as those involved in aging, as well as hunger, radiation, hormones and immunosuppressants. Notably, researchers have made great progress in examining the numerous mechanisms that contribute to immune suppression and have provided a future direction for research and a novel manner of developing immune-modulating drugs (112). It must be noted that there are differences between immunosenescence, immune atrophy and immunosuppression; therefore, these situations should be treated differently when developing specific molecular signaling pathways and in targeted drug development. The development of novel drugs, and signal transduction research concerning these mechanisms, may benefit patients that are immunocompromised, in a pathological state, or a combination, to reduce the side effects of other drugs on the thymus.

During the last decade, the development of proteomics technology and protein targets for drug generation and drug screening mechanisms has provided novel tools for biomedical research (113,114). There have been several reports regarding thymic molecular mechanisms using proteomics technology; therefore, a more comprehensive analysis of protein alterations in the thymus under various circumstances has been established. This, combined with the related molecule-function databases, including UniProt, the Kyoto Encyclopedia for Genes and Genomes and the Gene Ontology database, has enabled protein network data analysis to screen for known or predicted drug-protein or protein-protein interactions in the thymus. A greater understanding of the mutual regulation of protein molecules may allow the prediction of possible molecular drug targets and drug development pathways. Existing proteomics studies have provided some pathways for protein regulation of signal transduction. These pathways are intricate webs of downstream intracellular signaling events that ultimately result in specific thymic immune response stresses. This understanding may provide novel ways of treating immunological diseases by targeting the stress protein molecules in the thymus, and may be useful in improving the functionality of the thymus. Collectively, these studies suggest that the markedly complex action mechanisms underlying immunomodulatory effects in the thymus are a promising therapeutic target for treatment of the immune system.

Acknowledgements

This review was supported by the Young Scientists Fund of the National Natural Science Foundation of China (grant no. 81403395), the Traditional Chinese Medicine Bureau of Guangdong Province [grant no. (2014) 539] and the Specific Research Fund for TCM Science and Technology of Guangdong Provincial Hospital of Chinese Medicine (grant nos. YN2015QN09, YN2016QJ11 and YN2015QN12).