2025년 노벨의학상 '면역관용' Treg cell

[문형철]

Collection  06 October 2025

Nobel Prize in Physiology or Medicine 2025

The 2025 Nobel Prize in Physiology or Medicine has been awarded jointly to Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi “for their discoveries concerning peripheral immune tolerance”.

Immune responses protect us against infections but if they are not properly controlled can cause tissue damage and autoimmune disease. Shimon Sakaguchi first identified the immune cells that we now refer to as ‘regulatory T cells’ as having a crucial role in protecting the body against immune attack and thus preventing autoimmune disease. Mary Brunkow and Fred Ramsdell then discovered that mutations in the FOXP3 gene in both mice and humans result in severe autoimmune disease, and Sakaguchi later linked these discoveries by showing that the development and function of regulatory T cells depend on FOXP3. Together, these discoveries help to explain how immune tolerance to ‘self’ tissues is maintained in the periphery, which has implications for autoimmune disease, cancer and transplantation, and holds great therapeutic promise.

To celebrate the award and recognize the achievements of the Nobel Laureates, Nature Portfolio presents a Collection of publications from the prize winners, essential reviews on the topic, news features that put the research into context, and related advances from other researchers.

컬렉션 2025년 10월 6일

2025년 노벨 생리학·의학상2025년 노벨 생리학·의학상은 “말초 면역 관용에 관한 발견”으로 메리 E. 브런코우, 프레드 램스델, 시몬 사카구치에게 공동 수여되었습니다.

면역 반응은 감염으로부터 우리를 보호하지만,
제대로 통제되지 않으면 조직 손상과 자가면역 질환을 유발할 수 있습니다.

시몬 사카구치는
현재 '조절 T 세포'로 불리는 면역 세포가
면역 공격으로부터 신체를 보호하고
자가면역 질환을 예방하는 데 핵심적인 역할을 한다는 사실을 최초로 확인했습니다.

메리 브런코우와 프레드 램스델은
쥐와 인간 모두에서 FOXP3 유전자의 돌연변이가 심각한 자가면역 질환을 유발한다는 사실을 발견했으며,
사카구치는 이후 조절 T 세포의 발달과 기능이 FOXP3에 의존한다는 점을 입증함으로써
이 두 발견을 연결했습니다.

이러한 발견들은 함께
‘자신’ 조직에 대한 면역 관용이 말초에서 어떻게 유지되는지 설명하는 데 기여하며,
이는 자가면역 질환, 암 및 이식에 대한 시사점을 제공하며 치료적 가능성을 크게 열어줍니다.

노벨상 수상자들의 업적을 기리고 축하하기 위해
네이처 포트폴리오는 수상자들의 논문 모음집, 해당 주제에 대한 핵심 리뷰, 연구를 맥락에 맞게
소개하는 뉴스 특집, 그리고 다른 연구자들의 관련 진전 사항을 제공합니다.

The immune system is a marvel of intricate checks and balances, enabling robust defences against infections while, in most cases, avoiding destructive responses against the body’s own tissues.

면역 체계는 

정교한 견제와 균형의 경이로움으로, 

감염에 대한 강력한 방어 기능을 가능하게 하면서도 

대부분의 경우 신체 자체 조직에 대한 파괴적인 반응을 피합니다.

marvel of intricate checks and balances

How is this balance maintained?

This question has puzzled immunologists for more than a century. Through a combination of insightful observations and carefully designed experiments, this year’s Laureates of the Nobel Prize in Physiology or Medicine, Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi, made discoveries that provided critical answers. By defining CD4+CD25+FOXP3+ regulatory T cells (Treg cells) and their importance in the control of self-reactive responses, their work decisively launched the field of Treg cell-mediated peripheral immune tolerance. The story is one of scientific curiosity, persistent investigations and critical discoveries that have revolutionized the understanding of immune regulation, with relevance for self-tolerance, autoimmunity and tumour evasion.

이 균형은 어떻게 유지될까요? 

이 질문은 

1세기 이상 면역학자들을 당혹스럽게 해왔습니다.

통찰력 있는 관찰과 신중하게 설계된 실험을 통해, 

올해 노벨 생리학·의학상 수상자인 

메리 E. 브런코우, 프레드 램스델, 시몬 사카구치는 

중요한 해답을 제시하는 발견을 이루었습니다.

CD4+CD25+FOXP3+ 조절 T 세포(Treg 세포)를 정의하고 

자가 반응성 반응 조절에서의 중요성을 규명함으로써, 

그들의 연구는 Treg 세포 매개 말초 면역 관용 분야를 결정적으로 개척했습니다.

CD4+CD25+FOXP3+ regulatory T cells (Treg cells) 

control of self-reactive responses

Treg cell-mediated peripheral immune tolerance

이 이야기는 

과학적 호기심, 끈질긴 연구, 그리고 면역 조절에 대한 이해에 

혁명을 일으킨 중요한 발견들로 이루어져 있으며, 

자가 내성, 자가 면역 및 종양 회피와 관련이 있습니다.

A robust immune system is critical for our survival and health. Without it, we would be highly vulnerable, as we are constantly exposed to microbes in our environment. The immediate response following an infection is provided by the innate immune system, while the adaptive immune system requires a few days to be mobilised. A hallmark of the adaptive immune system is its ability to “remember” pathogens we have been exposed to previously, so we can respond quicker and more efficiently the next time we encounter the same agent. Immunological memory is mediated by our T cells and B cells, which recognise foreign structures (antigens). The recognition is mediated by antigen receptors called T cell receptors (TCRs) and B cell receptors (BCRs/membrane-bound anti bodies), which are generated during lymphocyte development. Each lymphocyte has its own unique antigen receptor and collectively, this provides our immune systems with an enormous capacity to recognise any potential foreign structure we may encounter during our lifetime.

강력한 면역 체계는 

우리의 생존과 건강에 매우 중요합니다. 

그것이 없다면, 

우리는 환경 속 미생물에 지속적으로 노출되어 있기 때문에 매우 취약해질 것입니다.

감염 직후의 즉각적인 반응은 

선천성 면역 체계에 의해 제공되는 반면, 

후천성 면역 체계는 동원되기까지 며칠이 걸립니다. 

후천성 면역 체계의 특징은 

이전에 노출된 병원체를 “기억”하는 능력으로, 

다음에 동일한 병원체를 접했을 때 

더 빠르고 효율적으로 대응할 수 있게 합니다.

이 면역학적 기억은

 T 세포와 B 세포에 의해 매개되며, 

이들은 외래 구조물(항원)을 인식합니다.

이 인식은 

T 세포 수용체(TCR) 및 B 세포 수용체(BCR/막 결합 항체)라고 하는 항원 수용체에 의해 매개되며, 

이는 림프구 발달 과정에서 생성됩니다.

각 림프구는 고유한 항원 수용체를 가지고 있으며, 

이로 인해 우리 면역 체계는 일생 동안 접할 수 있는 

모든 잠재적 이물질 구조를 인식할 수 있는 막대한 능력을 갖추게 됩니다.

How is antigen recognition achieved?

The question of how we can make so many different antigen receptors was a mystery prior to the 1980s. It was clear that there was not enough space in the genome for a “one gene-one receptor” explanation. The mechanisms that finally explained how highly diverse BCR repertoires are generated came from Susumu Tonegawa, who received the Nobel Prize in Physiology or Medicine in 1987. He demonstrated that a large set of germlineencoded genes, the so-called variable (V), diversity (D), and joining (J) genes, are assembled in a combinatorial manner when B cells are formed, resulting in a unique pair of heavy (VDJ) and light (VJ) chains that make up the functional receptor in each cell (Tonegawa 1983). This remarkable set of findings was soon followed by the identification of genomic loci encoding the TCR V, D, and J genes, by the groups of Tak Mak at the University of Toronto and Mark Davis at Stanford University (Hedrick et al. 1984; Yanagi et al. 1984). 

Like BCRs, TCRs are formed by recombination of V, 2 D and J genes, theoretically giving rise to more than 1015 distinct receptors in each individual. TCRs consist of either an alpha (a) chain paired with a beta (b) chain (Figure 1), or a gamma (g) chain paired with a delta (d) chain, yielding either ab T cells or a gd T cells. Most of our T cells are ab T cells, including the regula-tory T cells that are central to this  year’s Nobel Prize in Physiology or Medicine.

항원 인식은 어떻게 이루어지는가? 

1980년대 이전에는 어떻게 그렇게 다양한 항원 수용체를 만들 수 있는지에 대한 질문이 수수께끼였다. “하나의 유전자-하나의 수용체”라는 설명으로는 게놈에 충분한 공간이 없다는 것이 분명했습니다. 매우 다양한 BCR 레퍼토리가 어떻게 생성되는지 최종적으로 설명한 메커니즘은 1987년 노벨 생리학·의학상을 수상한 도네가와 스스무(Susumu Tonegawa)가 제시했습니다. 생리학·의학상 수상자입니다. 그는 B세포가 형성될 때, 소위 가변(V), 다양성(D), 결합(J) 유전자로 불리는 대규모 생식세포 유전자 집합이 조합적 방식으로 조립되어 B 세포가 형성될 때 조합적 방식으로 조립되어 각 세포의 기능적 수용체를 구성하는 고유한 중쇄(VDJ) 및 경쇄(VJ) 쌍을 생성한다는 것을 입증했습니다(토네가와 1983).  이 놀라운 일련의 발견에 이어, 토론토 대학의 Tak Mak 연구팀과 스탠퍼드 대학의 Mark Davis 연구팀이 TCR V, D, J 유전자를 암호화하는 게놈 위치를 확인했습니다 (Hedrick et al. 1984;    Yanagi    et    al.    1984).    

BCR과 마찬가지로 TCR도 V, D 및 J 유전자의 재조합에 의해 형성되며, 이론적으로 각 개인마다 1015개 이상의 서로 다른 수용체가 생성됩니다. TCR은 알파(α) 사슬과 베타(β) 사슬이 쌍을 이루거나(그림 1), 감마(γ) 사슬과 델타(δ) 사슬이 쌍을 이루며, 이로 인해 ab T 세포 또는 gd T 세포가 생성됩니다. 우리 T 세포의 대부분은 ab T 세포이며, 여기에는 올해 노벨 생리학·의학상 수상에 핵심적인 역할을 한 조절 T 세포도 포함됩니다.

Physiology or Medicine together with Baruj Benacerraf.

The MHC molecules were discovered by their capacity to induce graft rejection following transplantation, but their physiological function(s) remained an enigma. Critical findings were provided by Peter Doherty and Rolf Zinkernagel in the 1970s when they demonstrated that T cells only respond to Work performed in the 1970s demonstrated that ab T cells can be divided into subsets that play complementary roles in the immune response (Gershon and Kondo 1970; Reinherz et al. 1979). The two main types are CD4+ T helper cells, which provide critical supportive functions for both the cellular and humoral arms of the immune system, and CD8+ cytotoxic T cells, which recognise and eliminate infected cells and tumour cells. Both types of T cells recognise antigens presented by Major Histocompatibility Complex (MHC) molecules present. The gene clusters encoding the MHC molecules had been discovered during the 1940s and 1950s, first in mice by George Snell (Snell 1948), and a decade later, the corresponding human genes encoding the Human Leukocyte Antigen (HLA) molecules were described by Jean Dausset (Dausset 1958), earning them the 1980 Nobel Prize in Physiology or Medicine together with Baruj Benacerraf. The MHC molecules were discovered by their capacity to induce graft rejection following transplantation, but their physiological function(s) remained an enigma. Critical findings were provided by Peter Doherty and Rolf Zinkernagel in the 1970s when they demonstrated that T cells only respond to viruses in the context of MHC molecules, referred to as MHC restriction (Zinkernagel 1974; Zinkernagel and Doherty 1974, 1975), a finding, which earned them the Nobel Prize in Physiology or Medicine in 1996. This intriguing finding was further explained by experiments performed by Alain Townsend who demonstrated that CD8+ cytotoxic T cells recognise peptides presented by MHC class I molecules, while CD4+ T helper cells recognise peptides presented by MHC class II molecules (Townsend, Gotch, and Davey 1985; Townsend et al. 1986), Emil R. Unanue (Babbitt et al. 1985), with structural studies performed by Pamela Bjorkman performed by Pamela Bjorkm and Don Wiley (Bjorkman et al. 1987).

생리학 또는 의학 분야, 바루즈 베나세라프와 공동 수상.

MHC 분자는 

이식 후 이식편 거부 반응을 유발하는 능력으로 발견되었으나,

 그 생리적 기능은 수수께끼로 남아 있었다. 

1970년대에 피터 도허티와 롤프 징커나겔이 

T 세포가 항원 특이적 T 세포(ab T 세포)에만 반응한다는 것을 입증하면서 

결정적인 발견이 이루어졌다. 

1970년대에 수행된 연구는 

ab T 세포가 면역 반응에서 상호 보완적인 역할을 하는 하위 집합으로 나눌 수 있음을 보여주었다(Gershon and Kondo 1970; Reinherz et al. 1979). 

두 가지 주요 유형은 

면역 체계의 세포성 및 체액성 반응 모두에 필수적인 보조 기능을 제공하는 

CD4+ T 헬퍼 세포와 감염된 세포 및 종양 세포를 인식하고 제거하는 

CD8+ 세포독성 T 세포이다. 

두 유형의 T 세포 모두 

주요 조직적합성 복합체(MHC) 분자에 의해 제시된 항원을 인식한다. 

MHC 분자를 암호화하는 

유전자 군집은 1940년대와 1950년대에 발견되었는데, 

조지 스넬(George Snell)이 쥐에서 최초로 발견했으며(Snell 1948), 

이후 10년 뒤 장 도세(Jean Dausset)가 인간 백혈구 항원(HLA) 분자를 암호화하는 

대응 인간 유전자를 기술하였으며(Dausset 1958),

 이 공로로 바루지 베나세라프(Baruj Benacerraf)와 함께 

1980년 노벨 생리학·의학상을 수상하였습니다. 

MHC 분자는 

이식 후 이식편 거부 반응을 유발하는 능력으로 발견되었으나,

 그 생리적 기능은 수수께끼로 남아 있었습니다. 

1970년대에 피터 도허티와 롤프 진커나겔이 결정적인 발견을 제공했는데, 

그들은 T 세포가 MHC 분자(MHC 제한이라고 함)의 맥락에서만 

바이러스에 반응한다는 것을 입증했습니다 (Zinkernagel 1974; Zinkernagel and Doherty 1974, 1975)이라는 개념을 제시했으며, 

이 발견으로 그들은 1996년 노벨 생리학·의학상을 수상했다. 

이 흥미로운 발견은 

알랭 타운센드의 실험을 통해 더욱 명확해졌습니다. 

그는 CD8+ 세포독성 T 세포가 MHC I형 분자에 의해 제시된 펩타이드를 인식하는 반면, 

CD4+ T 헬퍼 세포는 MHC II형 분자에 의해 제시된 펩타이드를 인식한다는 것을 입증했습니다(Townsend, Gotch, and Davey 1985; 타운센드 외 1986), 에밀 R. 우나누에(바빗 외 1985), 

그리고 파멜라 비요크만과 돈 와일리가 수행한 구조 연구(비요크만 외 1987)를 통해 더욱 명확해졌다.

While the generation of vast BCR and TCR diversity maximises the capacity of our immune systems to recognize foreign antigens, it comes at a cost, as some receptors inadvertently recognise self-antigens – a phenomenon that Paul Ehrlich, 1908 Nobel Prize Laureate, described as “horror autotoxicus”. It would turn out to be a major challenge to unravel the molecular basis for severe autoimmune manifestations, but from the work of Ehrlich and others, we know that clinicians and researchers already in the early 1900s recognised the risks associated with a powerful immune system. They realised that elucidating the cellular and molecular mechanisms underlying immune regulation would be crucial for understanding immunemediated diseases and for the developmen treatments against these diseases.

광범위한 BCR 및 TCR 다양성의 생성은

우리 면역 체계가 외래 항원을 인식하는 능력을 극대화하지만,

일부 수용체가 의도치 않게 자가 항원을 인식하는 대가를 치르게 된다.

1908년 노벨상 수상자인 폴 에를리히가

“자가독성 공포(horror autotoxicus)”라고 묘사한 현상이다.

심각한 자가면역 증상의 분자적 기전을 규명하는 것은 큰 도전으로 드러났지만,

에를리히 등의 연구를 통해 우리는

1900년대 초반 이미 임상의와 연구자들이

강력한 면역 체계와 관련된 위험성을 인지하고 있었음을 알 수 있다.

그들은 면역 조절의 기초가 되는 세포적·분자적 기전을 밝히는 것이

면역 매개 질환을 이해하고 이에 대한 치료법을 개발하는 데 결정적일 것임을 깨달았다.

How is immune tolerance achieved?

So, how is immune tolerance achieved and maintained? The first experiments to address this question were performed by Ray Owen, who published his findings in Science in 1945 (Owen 1945). He studied calves with different blood groups that shared a common placental circulation and developed chimerism. He unexpectedly observed that they did not elicit an immune response to each other’s blood group antigens after birth, providing an important clue. Around the same time, Sir Frank Macfarlane Burnet wrote: “If, in embryonic life, expendable cells from a genetically different race are implanted and established, no antibody response should develop against the foreign antigen when the animal takes on an independent existence” (Burnet and Fenner 1949). Burnet thus predicted that immune tolerance must be acquired during embryonic or early life, although he was possibly already aware of Owen’s observations. In 1953, Peter B. Medawar and co-workers at University College, University of London published results from experiments in which foetuses of one inbred mouse strain were inoculated with cells from a second strain (Billingham, Brent, and Medawar 1953). In these experiments, skin grafts from the second strain were accepted after birth of the mice, but grafts from a third unrelated mouse strain were rejected. They proposed that this mechanism was due to “actively acquired tolerance”. The same year, the Czechoslovakian scientist Milan Hašek reported findings consistent to those of Owen when studying eggs wherein the vascular systems of chick embryos had been joined, a procedure known as parabiosis (Hašek 1953). These studies were published in a local scientific journal in Russian a  and were overlooked for a long time.

면역 관용은 어떻게 달성되는가?

그렇다면 

면역 관용은 어떻게 달성되고 유지될까? 

이 질문에 대한 최초의 실험은 레이 오웬(Ray Owen)이 수행했으며, 

그는 1945년 《사이언스》에 연구 결과를 발표했다(Owen 1945). 

그는 서로 다른 혈액형을 가진 송아지들이 

공통 태반 순환을 공유하며 키메라 현상을 일으키는 것을 연구했다. 

그는 출생 후 서로의 혈액형 항원에 대해 

면역 반응을 일으키지 않는다는 예상치 못한 관찰을 통해 중요한 단서를 제공했다. 

동시에 프랭크 맥팔레인 버넷 경은 

이렇게 기술했습니다: 

“배아기 동안 유전적으로 다른 종의 소모성 세포가 이식되어 정착된다면, 

동물이 독립적인 존재가 되었을 때 이물질 항원에 대한 항체 반응이 발생하지 않아야 한다”(Burnet and Fenner 1949). 

버넷은 오웬의 관찰을 이미 알고 있었을 가능성이 있음에도 불구하고, 

면역 관용이 반드시 배아기나 생애 초기 단계에서 획득되어야 한다고 예측했습니다. 

1953년, 런던 대학교 유니버시티 칼리지의 피터 B. 메다워와 공동 연구진은 

한 근친 교배 마우스 계통의 태아에 다른 계통의 세포를 접종한 실험 결과를 발표했다(Billingham, Brent, and Medawar 1953). 

이 실험에서 

두 번째 계통의 피부 이식편은 마우스 출생 후 수용되었으나, 

제3의 무관한 마우스 계통의 이식편은 거부되었다. 

그들은 이 메커니즘이 “능동적으로 획득된 내성”에 기인한다고 제안했다. 

같은 해 체코슬로바키아 과학자 밀란 하셰크는 병생(parabiosis)으로 알려진 절차로 

병아리의 혈관계를 연결한 알을 연구하며 오웬의 결과와 일치하는 발견을 보고했다(Hašek 1953). 

이 연구들은 

러시아어로 된 지역 과학 저널에 게재되었으며 

오랫동안 간과되었다.

Soon thereafter, Burnet published an influential paper on clonal selection (Burnet 1957), proposing that selection occurred at the cellular level rather than, as commonly believed at the time, at the antibody level. He expanded these ideas, which mainly related to positive selection of immune cells (Burnet 1959), and in 1960, the Nobel Prize in Physiology or Medicine was awarded to Sir Frank Macfarlane Burnet and Peter B. Medawar for their “discovery of acquired immunological tolerance”. Burnet later amended his theory to include negative selection, i.e., the removal of undesired T cells from the immune repertoire as a mechanism for acquired immune tolerance to self (Burnet 1962; Burnet 1969). 

그 직후 버넷은 클론 선택에 관한 영향력 있는 논문(Burnet 1957)을 발표하며, 당시 일반적으로 믿어지던 항체 수준이 아닌 세포 수준에서 선택이 일어난다고 제안했다. 그는 주로 면역 세포의 양성 선택과 관련된 이러한 아이디어를 확장했으며(Burnet 1959), 1960년에는 프랭크 맥팔레인 버넷 경과 피터 B. 메다워가 “획득된 면역학적 내성 발견”으로 노벨 생리학·의학상을 수상했다. 버넷은 이후 자신의 이론을 수정하여 부정적 선택, 즉 자가 면역 관용 획득의 메커니즘으로서 면역 레퍼토리에서 원치 않는 T 세포를 제거하는 과정을 포함시켰다(Burnet 1962; Burnet 1969).

Notably, the function of the thymus (and hence also the existence of T cells) had remained obscure until Jacques Miller, then at the Chester Beatty Research Institute in London, demonstrated that neonatal thymectomy in mice resulted in severe immune deficiency and the absence of specific lymphocyte subsets (Miller 1961b, 1961a). More than 20 years later, Philippa Marrack and John W. Kappler, then at the National Jewish Center for Immunology and Respiratory Medicine in Denver, USA, and Harald von Boehmer and coworkers at the Basel Institute for Immunology in Switzerland, provided experimental evidence that self-reactive T cells are eliminated by negative selection in the thymus (Kappler, Roehm, and Marrack 1987) (Kisielow et al. 1988). In the following years, investigators sought to understand the molecular basis of central tolerance, where self-reactive T cells are deleted in the thymus. An important step was the identification of the AIRE (autoimmune regulator) gene by two consortia, one led by Leena Peltonen (Finnish-German Apeced Consortium 1997) using a large cohort of patients with the rare disorder autoimmune polyendocrine syndrome type 1 (APS-1) – also named autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED) – collected by the Finnish paediatrician Jaakko Perheentupa (Perheentupa 1996), and the other by the team of Nobuyoshi Shimizu (Nagamine et al. 1997). Mark Anderson, Christophe Benoist and Diane Mathis were the first to explain how AIRE, a transcription factor, enables the elimination of self-reactive T-cells in the thymus (Anderson et al. 2002).

특히, 흉선의 기능(그리고 따라서 T 세포의 존재)은 런던 체스터 비티 연구소의 자크 밀러가 생후 쥐의 흉선 적출이 심각한 면역 결핍과 특정 림프구 하위 집단의 부재를 초래함을 입증하기 전까지 불분명했다(Miller 1961b, 1961a). 20여 년 후, 미국 덴버 소재 국립 유대인 면역학 및 호흡기 의학 센터의 필리파 마랙(Philippa Marrack)과 존 W. 카플러(John W. Kappler), 그리고 스위스 바젤 면역학 연구소의 하랄트 폰 보머(Harald von Boehmer)와 동료들은 자가반응성 T 세포가 흉선에서 음성 선택을 통해 제거된다는 실험적 증거를 제시했다(Kappler, Roehm, and Marrack 1987) (Kisielow et al. 1988). 

이후 연구자들은 흉선에서 자가반응성 T 세포가 제거되는 중추적 내성의 분자적 기전을 규명하기 위해 노력했다. 중요한 진전은 두 연구 컨소시엄에 의해 AIRE(자가면역 조절자) 유전자가 확인된 것이었다. 하나는 리나 펠토넨(Leena Peltonen)이 이끈 핀란드-독일 APECED 컨소시엄(1997)으로, 희귀 질환인 자가면역 다발성 내분비 증후군 1형(APS-1) – 또한 자가면역 다발성 내분비병증-칸디다증-외배엽 이영양증(APECED) (APECED)로도 알려진 희귀 질환 환자 대규모 코호트를 활용하여 AIRE(자가면역 조절자) 유전자를 확인한 것이었다. 마크 앤더슨(Mark Anderson), 크리스토프 베노이스트(Christophe Benoist), 다이앤 매티스(Diane Mathis)는 전사 인자인 AIRE가 흉선에서 자가 반응성 T 세포를 제거하는 방법을 최초로 설명했습니다(Anderson et al. 2002).

They showed that AIRE activates the expression‎ of tissue-specific antigens in medullary thymic epithelial cells (mTECs), thereby allowing newly formed T cells to be tested for potential self-reactivity. In the absence of significant self-reactivity, the T cells are left intact and exit the thymus to enter the circulation. In contrast, strongly selfreactive T cells undergo elimination through apoptosis. The elimination of self-reactive, potentially harmful T cells from the naïve T cell repertoire became known as central tolerance, a fundamental pillar of the adaptive immune system. For many years, central tolerance was believed to be the sole mechanism preventing T cells from reacting against our own tissues. Although AIRE-mediated negative selection is robust, it is not absolute and some selfreactive T cells escape deletion in the thymus and enter the circulation. This led researchers to speculate that additional mechanisms must exist to contain these cells. A major question was whether a specialised suppressive T cell subset existed, which we will return to below, but researchers also wished to understand immune tolerance mechanisms in a broader sense, including those involving other immune cells.

그들은 AIRE가 골수성 흉선 상피세포(mTECs)에서 조직 특이적 항원의 발현을 활성화하여 새로 생성된 T 세포가 잠재적 자가반응성을 검사받을 수 있게 함을 보여주었다. 상당한 자가반응성이 없는 경우, T 세포는 손상되지 않은 채로 남아 흉선을 떠나 순환계로 진입한다. 반면, 강한 자가반응성을 보이는 T 세포는 세포사멸을 통해 제거된다. 자신 조직에 반응할 가능성이 있는 유해한 자가반응성 T 세포를 미경험 T 세포 군집에서 제거하는 이 과정은 적응 면역 체계의 핵심 기둥인 '중추적 내성(central tolerance)'으로 알려지게 되었다. 오랫동안 중추적 내성은 T 세포가 우리 자신의 조직에 반응하는 것을 막는 유일한 메커니즘으로 여겨졌다. AIRE 매개 음성 선택은 강력하지만 절대적이지는 않아 일부 자가반응성 T 세포는 흉선에서 제거를 피하고 순환계로 진입한다. 이로 인해 연구자들은 이러한 세포들을 억제하기 위한 추가적인 메커니즘이 존재해야 한다고 추측하게 되었다. 주요 의문점은 특수한 억제성 T 세포 하위 집합이 존재하는지 여부였으며, 이는 아래에서 다시 다루겠지만, 연구자들은 또한 다른 면역 세포들이 관여하는 메커니즘을 포함하여 보다 광범위한 의미에서의 면역 관용 메커니즘을 이해하고자 했다.

Peripheral immune mechanisms in play

One model concerned the concept of costimulation, which suggested that additional cell-to-cell interactions, beyond TCRMHC/peptide binding, were required to activate T cells. Early work by Mark Jenkins and Ron Schwartz at the National Institutes of Health, Bethesda, USA, demonstrated that TCR engagement in the absence of co-stimulation caused T cells to become unresponsive, or anergic (Jenkins and Schwartz 1987).

주변 면역 메커니즘의 작용

한 가지 모델은 TCR-MHC/펩타이드 결합을 넘어선 추가적인 세포 간 상호작용이 T 세포 활성화를 위해 필요하다는 공동자극(costimulation) 개념과 관련되었습니다. 미국 국립보건원(NIH) 베데스다 캠퍼스의 마크 젠킨스(Mark Jenkins)와 론 슈워츠(Ron Schwartz)의 초기 연구는 공동자극 없이 TCR이 결합할 경우 T 세포가 반응하지 않거나 무반응 상태(anergic)가 된다는 것을 보여주었습니다(Jenkins and Schwartz 1987).

This led to the identification of CD28 on T cells by the laboratories of Craig Thompson (Turka et al. 1990) and James Allison (Gross, St John, and Allison 1990), and its interaction with CD80 or CD86 on antigen-presenting cells (APCs) to mediate a positive co-stimulatory signal (Linsley, Clark, and Ledbetter 1990). Allison was awarded the Nobel Prize in Physiology or Medicine in 2018, for his discovery that 5 antibodies against the negative co-stimulatory molecule, CTLA4 (CD152), which also binds CD80 and CD86, can active the T cell response against tumours. Many investigators subsequently contributed to the field of costimulation, as reviewed in Chen et al. (Chen and Flies 2013), firmly establishing this extra layer of control. Another related line of investigation focused on a class of APCs called dendritic cells (DCs), which play a major role in activating naïve T cells during immune priming. In the early 2000s, one of the Laureates of the Nobel Prize in Physiology or Medicine 2011, Ralph Steinman, showed that the targeting of antigen to DCs in the absence of co-stimulation induced T cell tolerance (Hawiger et al. 2001). He named these cells tolerogenic DCs (Steinman, Hawiger, and Nussenzweig 2003). In even earlier work addressing B cellmediated tolerance, Christopher Goodnow and Antony Basten used BCR transgenic mice to demonstrate the concept of B cell clonal anergy (Goodnow et al. 1988).

이를 계기로 크레이그 톰슨(Craig Thompson) (Turka et al. 1990)과 제임스 앨리슨(James Allison) 연구실(Gross, St John, and Allison 1990)에 의해 T 세포의 CD28이 확인되었으며,

 항원제시세포(APC)의 CD80 또는 CD86과의 상호작용을 통해 양성 공동자극 신호를 매개한다는 사실이 밝혀졌다(Linsley, Clark, and Ledbetter 1990).

 앨리슨은 2018년 생리학·의학 노벨상을 수상했는데, 

이는 CD80 및 CD86에도 결합하는 음성 공동자극 분자 CTLA4(CD152)에 대한 5

가지 항체가 종양에 대한 T 세포 반응을 활성화할 수 있다는 그의 발견 덕분이었다. 

이후 많은 연구자들이 공동자극 분야에 기여했으며(Chen et al. 2013), 

이를 통해 이 추가적인 조절 계층이 확고히 정립되었다. 

또 다른 관련 연구 분야는 면역 초기 단계에서 미경험 T 세포 활성화에 주요 역할을 하는 수지상 세포(DCs)라는 APC 유형에 집중되었다. 

2000년대 초, 2011년 노벨 생리학·의학상 수상자 중 한 명인 랄프 스타인만(Ralph Steinman)은 공동자극 없이 항원을 DC에 표적화하면 T 세포 내성이 유도된다는 사실을 보여주었다(Hawiger et al. 2001). 

그는 이러한 세포를 내성유도성 DC(tolerogenic DCs)라고 명명했다(Steinman, Hawiger, and Nussenzweig 2003) . 더 이른 시기에 B 세포 매개 내성을 연구한 크리스토퍼 굿나우(Christopher Goodnow)와 앤토니 배스턴(Antony Basten)은 BCR 트랜스제닉 마우스를 이용해 B 세포 클론 무반응(B cell clonal anergy) 개념을 입증했습니다(Goodnow et al. 1988).

Regulatory B cells that produce IL-10, an important cytokine for dampening immune responses, have also been described. This is a growing and intriguing field, as comprehensively reviewed (Lund et al. 2005). Thus, there are multiple mechanisms of peripheral immune tolerance in place to safeguard us against undesired self-reactivity. One of the most important mechanisms involves regulatory T cells and we will now return to T cell-mediated peripheral tolerance against self, the topic of this year’s Nobel Prize in Physiology or Medicine.

면역 반응을 억제하는 중요한 사이토카인인 IL-10을 생성하는 조절 B 세포도 보고된 바 있다. 이는 포괄적으로 검토된 바와 같이(Lund et al. 2005) 성장 중인 흥미로운 분야이다. 따라서 원치 않는 자가 반응으로부터 우리를 보호하기 위한 말초 면역 관용의 다중 메커니즘이 존재한다. 가장 중요한 메커니즘 중 하나는 조절 T 세포와 관련되어 있으며, 이제 올해 노벨 생리학·의학상 주제가 된 자가반응에 대한 T 세포 매개 말초 내성으로 다시 돌아가 보겠습니다.

Suppressor T cells: a detour

In the 1970s, the concept of “suppressor T cells” had emerged, based on experiments showing that certain T cell populations could suppress immune responses in vitro and in vivo (Gershon and Kondo 1970). However, the field was plagued by inconsistent methodologies, a lack of specific markers, and the inability to definitively distinguish these cells from other T cell subsets. Suppressor cells were thought to be a CD8+ T cells subset, and the I-J locus in mice was reported to encode functionally important determinants of suppressor T cells. With the emergence of more accurate gene sequencing technologies, it became clear that the I-J locus did not exist (Kronenberg et al. 1983). As a result, enthusiasm waned, and the notion of suppressor T cells faced growing scepticism until the field eventually collapsed (Keating and Cambrosio 1997). However, some of the reported results were likely correct even though they were not sufficiently conclusive.

억제 T 세포: 우회 경로

1970년대, 특정 T 세포 집단이 시험관 내 및 생체 내에서 면역 반응을 억제할 수 있음을 보여주는 실험을 바탕으로 “억제 T 세포” 개념이 등장했습니다(Gershon and Kondo 1970). 그러나 이 분야는 일관성 없는 방법론, 특이적 표지자의 부재, 그리고 이러한 세포들을 다른 T 세포 하위 집합과 명확히 구분할 수 없는 문제로 어려움을 겪었습니다. 억제 세포는 CD8+ T 세포의 하위 집합으로 여겨졌으며, 생쥐의 I-J 유전자좌가 억제 T 세포의 기능적으로 중요한 결정 인자를 암호화한다고 보고되었습니다. 더 정확한 유전자 염기서열 분석 기술의 등장으로 I-J 유전자군이 존재하지 않음이 밝혀졌다(Kronenberg et al. 1983). 그 결과 열의가 식었고, 억제 T 세포 개념은 점점 더 회의적인 시각에 직면하다가 결국 이 분야는 붕괴되었다(Keating and Cambrosio 1997). 그러나 보고된 결과 중 일부는 충분히 결정적이지 않았음에도 불구하고 정확했을 가능성이 있다. 

The regulatory T cell renaissance

The field of immune regulation gained new traction in the late 1980s and 1990s with Shimon Sakaguchi and colleagues in Japan playing a pivotal role.

조절 T 세포의 부활 

1980년대 후반과 1990년대에 들어서 면역 조절 분야는 새로운 활력을 얻었는데, 일본에서 사카구치 시몬(坂口 志門)과 동료들이 중추적인 역할을 했다.

As early as 1969, Yasuaki Nishizuka and Teruyo Sakakura demonstrated that removal of the thymus from newborn mice day 3 postpartum led to spontaneous development of ovarian dysgenesis due to autoimmune ovarian insufficiency along with various other autoimmune diseases including gastritis and thyroiditis (Nishizuka and Sakakura 1969). In 1973, William J. Penhale extended these observations by showing that neonatal thymectomy of rats induced autoimmune thyroiditis with the development of thyroid autoantibodies (Penhale et al. 1973). He later demonstrated that the thyroiditis could be prevented if lymphocytes from healthy animals were injected into the thymectomized rats (Penhale et al. 1976). After completing his medical studies at Kyoto University, Shimon Sakaguchi joined Nishizuka’s laboratory at the Aichi Cancer Center Research Institute. In 1982, they provided evidence consistent with Penhale’s work in rats, that the autoimmune process in thymectomized mice could be abrogated by transferring a specific fraction of immune cells 6 from normal mice, characterized by expressing the surface marker CD5 (Lyt-1) and low levels of CD45RB (Sakaguchi, Takahashi, and Nishizuka 1982).

969년 초, 니시즈카 야스아키(西塚康昭)와 사카쿠라 데루요(榊原輝代)는 출생 후 3일차 신생 생쥐에서 흉선을 제거하면 자가면역성 난소 기능 부전으로 인한 난소 이형성증의 자연 발생과 함께 위염 및 갑상선염을 포함한 다양한 자가면역 질환이 동반된다는 사실을 입증하였다(Nishizuka and Sakakura 1969). 1973년 윌리엄 J. 펜헤일은 쥐의 신생아 흉선 절제술이 갑상선 자가항체 형성과 함께 자가면역성 갑상선염을 유발한다는 점을 보여줌으로써 이러한 관찰을 확장했다(Penhale et al. 1973). 그는 이후 건강한 동물의 림프구를 흉선 절제술을 받은 쥐에게 주입하면 갑상선염을 예방할 수 있음을 입증했다(Penhale et al. 1976). 사카구치 시몬은 교토 대학에서 의학 공부를 마친 후 아이치 암 센터 연구소의 니시즈카 연구실에 합류했다. 1982년, 그들은 쥐를 대상으로 한 Penhale의 연구와 일치하는 증거를 제시했는데, 흉선 적출 마우스에서 자가면역 과정은 정상 마우스에서 표면 마커 CD5(Lyt-1)를 발현하고 CD45RB 수준이 낮은 특정 면역 세포 분획을 이식함으로써 억제될 수 있다는 것이었습니다(Sakaguchi, Takahashi, and Nishizuka 1982).

Notably, these studies were performed using allosera to classify cells, before monoclonal antibodies directed against distinct cell surface markers became available. Thus, the toolbox available for detailed molecular examination of cell phenotypes was limited, but this would soon change. Because the question of immune tolerance is fundamental to our understanding of immunology, it attracted much interest, and many accomplished scientists joined the research field. With the increasing availability of monoclonal antibodies against cell surface antigens, Fiona Powrie and Don Mason at the University of Oxford demonstrated that CD4+ T helper lymphocytes expressing high levels of CD45RB induced a severe wasting disease, characterized by inflammatory infiltrates in liver, lung, stomach, thyroid and pancreas, when injected into athymic mice. In contrast, injection of the CD4+ lymphocyte subset expressing low levels of CD45RB protected the animals from disease (Powrie and Mason 1990). They concluded that functional heterogeneity and specialization within the peripheral CD4+ T cell population could account for mechanisms of immune regulation.

특히, 이러한 연구들은 특정 세포 표면 마커를 표적으로 하는 단일클론 항체가 등장하기 전, 동종 혈청을 이용해 세포를 분류하는 방식으로 수행되었다. 따라서 세포 표현형을 상세히 분자 수준에서 분석할 수 있는 도구 상자는 제한적이었으나, 이는 곧 변화할 운명이었다. 면역 관용의 문제는 면역학 이해의 근본적 주제이기에 많은 관심을 끌었고, 다수의 저명한 과학자들이 이 연구 분야에 참여하게 되었다. 세포 표면 항원에 대한 단일클론 항체의 이용 가능성이 높아짐에 따라, 옥스퍼드 대학의 피오나 포우리(Fiona Powrie)와 돈 메이슨(Don Mason)은 고수준의 CD45RB를 발현하는 CD4+ T 헬퍼 림프구가 무흉선 마우스에 주입될 때 간, 폐, 위, 갑상선 및 췌장에 염증성 침윤을 특징으로 하는 심각한 소모성 질환을 유발함을 입증했다. 반면, CD45RB 발현 수준이 낮은 CD4+ 림프구 하위 집합을 주입하면 동물들이 질병으로부터 보호받는 것으로 나타났다(Powrie and Mason 1990). 그들은 말초 CD4+ T 세포 집단 내 기능적 이질성과 전문화가 면역 조절 메커니즘을 설명할 수 있다고 결론지었다.

The first breakthrough – defining the critical subpopulation of T cells

Sakaguchi continued his diligent work to understand immune regulation. He aimed to further fractionate the CD5+/CD45RBlow T cells he had described in his earlier publication (Sakaguchi, Takahashi, and Nishizuka 1982) by separating the cell population based on additional surface markers. In a landmark 1995 study, Sakaguchi and co-workers showed that CD4+ T lymphocytes expressing the surface marker CD25, the alpha chain of the IL-2 receptor, possessed immune regulatory functions (Sakaguchi et al. 1995). When Balb/c athymic nude (nu/nu) mice were injected with CD4+ cells from spleen and lymph nodes depleted of CD25+ T cells from heterozygous Balb/c nu/+ mice, they developed histologically and serologically evident autoimmune diseases, including thyroiditis, gastritis, insulitis, adrenalitis, and polyarthritis. However, re-constitution with CD4+CD25+ T cells within a limited period after transfer of CD4+CD25- T cells prevented the development of autoimmunity (Figure 2). These findings indicated that the CD4+CD25+ T cells were essential for maintaining immune self tolerance. 

첫 번째 돌파구 – T 세포의 핵심 하위 집단을 규명하다

사카구치는 면역 조절을 이해하기 위한 꾸준한 연구를 이어갔다. 그는 이전 논문(Sakaguchi, Takahashi, and Nishizuka 1982)에서 기술한 CD5+/CD45RBlow T 세포를 추가 표면 마커를 기반으로 세포 집단을 분리하여 더 세분화하는 것을 목표로 했다. 1995년 획기적인 연구에서 사카구치와 공동 연구진은 표면 마커 CD25(IL-2 수용체의 알파 사슬)를 발현하는 CD4+ T 림프구가 면역 조절 기능을 보유함을 입증했다(Sakaguchi et al. 1995). Balb/c 무흉선 누드(nu/nu) 마우스에 이형접합 Balb/c nu/+ 마우스의 CD25+ T 세포를 제거한 비장 및 림프절의 CD4+ 세포를 주입했을 때, 갑상선염, 위염, 췌장염, 부신염 및 다발성 관절염을 포함한 조직학적으로 및 혈청학적으로 명백한 자가면역 질환이 발생했습니다. 그러나 CD4+CD25- T 세포 이식 후 제한된 기간 내에 CD4+CD25+ T 세포로 재구성하면 자가면역 발생을 예방할 수 있었다(그림 2). 이러한 결과는 CD4+CD25+ T 세포가 면역 자가내성 유지에 필수적임을 시사한다. 

This discovery provided robust evidence for the existence of a regulatory CD4+CD25+ T cell subset capable of dampening immune responses, a finding that was soon supported by results from the laboratory of Ethan Shevach at the National Institutes of Health, Bethesda, USA (Thornton and Shevach 1998) and others. The identification of CD4+CD25+ T cells marked a breakthrough in immunology and laid the foundation for further in-depth investigations. The term regulatory T cell had been occasionally used in the 1970s and 1980s (Baker 1975; Chaouat et al. 1982). However, it was only after Sakaguchi defined the CD4+CD25+ subset as regulatory T cells (Sakaguchi 2000) that the term Treg cells gained wide acceptance in the scientific community. Sakaguchi and co-workers demonstrated that the majority of the regulatory T cells originated in the thymus (Itoh et al. 1999). They also identified CTLA-4 as an additional marker of these cells, simultaneously with Powrie’s group, in backto-back publications (Read, Malmström, and Powrie 2000; Takahashi et al. 2000). In parallel investigations in transplantation biology, Bruce Hall and Susan Dorsch working in Sydney, Australia, described a lymphocyte subset with inhibitory function in Cyclosporin A-treated mouse recipients of heart allografts. Hall and Dorsch described these as CD4+ T cell (Hall, Jelbart, and Dorsch 1984; Hall et al. 1985) and later reported that they also expressed CD25+ (Hall et al. 1990). At the time, the fields of transplantation biology and immune tolerance had little overlap, and investigators in the two respective fields did not exchange information or consolidate their results on a frequent basis. Hall and Dorch did not investigate whether the cells they had identified played a role in self-tolerance under normal physiological conditions, in the absence of Cyclosporin A treatment. Thus, definitive evidence to explain immune tolerance in a broader sense was still lacking. As techniques developed and interest in immune regulation increased, researchers sought to better understand the origins, mechanisms and the defining characteristics of the cells identified by Sakaguchi. While CD25 proved to be a useful marker, it was also expressed, albeit at lower levels, on conventional activated effector T cells (Leonard et al. 1982; Uchiyama, Broder, and Waldmann 1981; Uchiyama et al. 1981), which limited its specificity for identifying the regulatory T cell subset. Experimental studies demonstrated that these cells could suppress the proliferation and cytokine production of conventional T cells through several mechanisms: cell-cell contact-dependent interactions, secretion of suppressive cytokines such as IL-10, IL-35 and TGFβ, and sequestration of IL-2, thereby depriving other T-cells of a critical growth factor (Goldmann et al. 2024). While the capacity of CD4+CD25+ T cells to maintain tolerance and prevent autoimmunity was known, scepticism remained and a definitive molecular marker was still missing, hampering progress in the field. This would change dramatically with the identification of a mechanism that selectively controls the development and function of the regulatory T cell subset. The second breakthrough – The scurfy mouse and the discovery of FOXP3 At the Department of Energy's Oak Ridge National Laboratory in Tennessee, as part of the Manhattan Project during the 1940s, researchers studied the effects of radiation on mice. Laboratory personnel noted a spontaneous mutant, which they named scurfy. This strain developed a serious autoimmune disease, and breeding studies revealed that the mutation was lethal if carried by males, while female mice were unaffected. Thus, it was concluded that the mutation responsible for 8 the autoimmune phenotype was located on the X-chromosome (