The 2025 Nobel Prize for Physiology or Medicine (for biologists only)

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(1) In 1984 I came to the United States for a PhD program in immunology at University of Illinois at Chicago. We used a textbook published that year by two Harvard immunologists: Emil R Unanue and Baruj Benacerraf, Textbook of Immunology. 2nd ed. Williams & Wilkins, 1984. (Benacerraf, received Nobel Prize in Medicine in 1980, also published, as the sole author, the first edition of Textbook of Immunology in 1980.)


(2) Nobel Prize in Physiology or Medicine 2025
https://www.nobelprize.org/prizes/medicine/2025/summary/

On the left margin of this home page (press "Advanced information") is
Gunilla Karlsson Hedestam G and Kämpe O, Immune Tolerance; The identification of regulatory T cells and FOXP3. Nobel committee in Physiology or Medicine, Oct 6, 2025 (under the heading "Scientific background 2025").
, which the committee for Nobel Prize in Physiology or Medicine, for the first time, wrote a detailed review of milestones in that regard -- a review intended for PhDs. The footnotes below are for this link

Note:
(a) "The mechanisms that finally explained how highly diverse BCR repertoires are generated came from Susumu TONEGAWA [利根川 進 (the 322 km-long 利根川 is the second longest river in Japan, after 信濃川)], who received the Nobel Prize in Physiology or Medicine in 1987. He demonstrated that a large set of germline encoded 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 [1952- ] at Stanford University (Hedrick et al. 1984; Yanagi et al. 1984). * * * Both types of T cells [CD4+ T  helper cells and CD8+ cytotoxic  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."
(i) Tak Wah MAK 麦 德华 (born in 1946 in Guangzhou, raised and educated in Hong Kong, moved with his parents to Wisconsin in mid-1960s)
(ii) George Davis Snell (1903 – 1996; worked at The Jackson Laboratory (which studied mice) in Bar Harbor on Mount Desert Island, Maine (1935- ) )
The Jackson Laboratory was named after Roscoe B Jackson
https://www.hemmings.com/stories/roscoe-b-jackson/
(a one-time head of Hudson Motor Car Co (1909-1954; based in Detroit; successor  American Motors Corp (AMC) )
, who funded construction of the first building and the first 5 years of operation.
(iii)
(A) Jean Dausset
https://en.wikipedia.org/wiki/Jean_Dausset
(1916 – 2009; French; at age 16 went to Lycée Michelet (Vanves) )
https://en.wikipedia.org/wiki/Lycée_Michelet_(Vanves)
(Vanves is a commune 5.6 km (3.5 mi) from the centre of Paris; the school was named after Jules Michelet
https://en.wikipedia.org/wiki/Jules_Michelet
) and obtained baccalauréat  
https://en.wikipedia.org/wiki/Baccalauréat
in mathematics after completing high school. He went to medical school in Paris but World War II broke out and he was enlisted in the army. Paris was liberated in 1944; He completed medical school in 1945. (In France, it takes at minimum nine years to obtain a medical degree (depending specialty) after high school.)
(B) French-English dictionary:
* lycée (noun masculine; from Ancient Greek via Latin)
https://en.wiktionary.org/wiki/lycée
(iv) Baruj Benacerraf
https://en.wikipedia.org/wiki/Baruj_Benacerraf
(1920 – 2011; Venezuelan-American; was born in Caracas and emigrated to US in 1940; BS from Columbia Univ in 1942 and Medical College of Virginia (public; now  Virginia Commonwealth University School of Medicine, in Richmond)
(A) Baruj Benacerraf (1920-2011). VCH School of Medicine, Dec 3, 2009 ("News")
https://medschool.vcu.edu/about/ ... nacerraf-1920-2011/
("Benacerraf was denied admission to over two dozen medical schools before a family friend secured him an interview with the assistant to the president of the Medical College of Virginia")
(B) Baruj Benacerraf papers. VCH Library, undated
https://archives.library.vcu.edu/repositories/3/resources/569
("Baruj Benacerraf was born in Caracas, Venezuela October 29, 1920, but raised in Paris, France. His family returned to Venezuela in 1939 due to the rise of the Nazi Party in neighboring Germany and the onset of World War II. A year later his family moved to New York City where Benacerraf enrolled at Columbia University and graduated in 1942. He planned to attend medical school but struggled to gain admission because of the Jewish quotas imposed by many universities. After being rejected by twenty five schools, Benacerraf was accepted by the Medical College of Virginia (MCV). A family friend connected to the college served as a personal reference for the aspiring physician. MCV and other medical schools across the United States compressed their curriculum into three years to accelerate the number of trained physicians available to support the war effort. Benacerraf entered medical school in 1942 and received his Doctor of Medicine just as the war was concluding in Europe in the spring of 1945. Following a one-year internship at Queen’s General Hospital in New York, he served in the United States Army before embarking on a career as a biomedical researcher. He was affiliated with a number of institutions from France to Massachusetts before accepting a faculty position at Harvard University in 1970. For the next twenty-one years Benacerraf continued his immunological research at Harvard as professor and researcher. * * * In the 1960s, Benacerraf carried out experiments on Guinea pigs which built upon Snell and Dausset's earlier work, and found that only some had responses to specific antigens. After selectively breeding the Guinea pigs, he discovered that this trait was genetic, and demonstrated that a previously unknown gene within the major histocompatibility complex existed and could be passed down between generations. This gene is now known as an immune-response gene, and is found within the same chromosome region that determines the formation of H antigens")
(C) Baruj Benacerraf
https://en.wikipedia.org/wiki/Baruj_Benacerraf
("He was recruited to the faculty of New York University (NYU), established his own laboratory * * * [At Harvard Medical School] He noticed that if antigens (something that causes a reaction with the immune system) were injected into animals with a similar heredity, two groups emerged: responders and non-responders. He then conducted further study and found that the dominant autosomal genes, termed the immune response genes, determined the response to certain antigens")
(D) major histocompatibility complex (MHC; gene and protein of the same name) is divided into Class I and Class II. The latter is expressed on the surface of antigen-presenting cells (APCs; typically macrophage).
(E) Janeway CA Jr, The Major Histocompatibility Complex and Its Functions. In Janeway CA Jr, Travers P, Walport M and Shlomchik MJ, Immunobiology; The immune system in health and disease. 5th ed. New York: Garland Science, 2001
https://www.ncbi.nlm.nih.gov/books/NBK10757/

four consecutive paragraphs:

" * * *Different allelic variants of MHC class II molecules also bind different peptides, but the more open structure of the MHC class II peptide-binding groove and the greater length of the peptides bound in it allow greater flexibility in peptide binding (see Section 3-17). It is therefore more difficult to predict which peptides will bind to MHC class II molecules.

"In rare cases, processing of a protein will not generate any peptides with a suitable motif for binding to any of the MHC molecules expressed by an individual. When this happens, the individual fails to respond to the antigen. Such failures in responsiveness to simple antigens were first reported in inbred animals, where they were called immune response (Ir) gene defects. These defects were identified and mapped to genes within the MHC long before the function of MHC molecules was understood. Indeed, they were the first clue to the antigen-presenting function of MHC molecules, although it was only much later that the ‘Ir genes’ were shown to encode MHC class II molecules. Ir gene defects are common in inbred strains of mice because the mice are homozygous at all their MHC loci and thus express only one type of MHC molecule from each gene locus. This limits the range of peptides they can present to T cells. Ordinarily, MHC polymorphism guarantees a sufficient number of different MHC molecules in a single individual to make this type of nonresponsiveness unlikely, even to relatively simple antigens such as small toxins. This has obvious importance for host defense.

"Initially, the only evidence linking Ir gene defects to the MHC was genetic—mice of one MHC genotype could make antibody in response to a particular antigen, whereas mice of a different MHC genotype, but otherwise genetically identical, could not. The MHC genotype was somehow controlling the ability of the immune system to detect or respond to specific antigens, but it was not clear at the time that direct recognition of MHC molecules was involved.

"Later experiments showed that the antigen specificity of T-cell recognition was controlled by MHC molecules. The immune responses affected by the Ir genes were known to be dependent on T cells, and this led to a series of experiments in mice to ascertain how MHC polymorphism might control T-cell responses. The earliest of these experiments showed that T cells could only be activated by macrophages or B cells that shared MHC alleles with the mouse in which the T cells originated. This was the first evidence that antigen recognition by T cells depends on the presence of specific MHC molecules in the antigen-presenting cell. The clearest example of this feature of T-cell recognition came, however, from studies of virus-specific cytotoxic T cells, for which Peter Doherty and Rolf Zinkernagel were awarded the Nobel Prize in 1996.

(v) Peter Doherty (immunologist)
https://en.wikipedia.org/wiki/Peter_Doherty_(immunologist)
(1940- ; Australian; PhD; did Nobel award-winning research at Australian National University in Canberra)
(vi) Rolf M Zinkernagel
(1944- ; Swiss; MD (1970), PhD (1975);  also did did Nobel award-winning research at Australian National University in Canberra while he was a student in the PhD program)

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(b) "How is immune tolerance achieved? * * * 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. * * * in 1960, the Nobel Prize in Physiology or Medicine was awarded to Sir Frank Macfarlane Burnet [1899 – 1985; Australian] and Peter B Medawar * ** the function of the thymus (and hence  also the existence of T cells[, which was named after thymus due to this finding]) 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 [T cells] (Miller 1961b, 1961a)."
(i) chimerism
(A) Reed W, Fiebig EW, Lee TH and Busch MP, Chapter 53 Post-Transfusion Engraftment Syndromes: Microchimerism and TA-GVHD. In Hillyer CD, Silberstein LE, Ness PM, Anderson KC, and Roback JD, Blood Banking and Transfusion Medicine; Basic principles and practice. 2nd ed. Churchill Livingstone, 2006.
https://www.sciencedirect.com/sc ... 9780443069819500582

three consecutive paragraphs:

"A chimera is a creature that harbors cells or tissues derived from another individual. In Greek mythology, the chimera was a beast with a lion's head and foreparts, a goat's body, and a serpent's tail. Medical research on chimerism can be traced to Ray Owen, who was born on a Wisconsin dairy farm in 1915. After studying agriculture and animal husbandry at the University of Wisconsin, he joined the faculty in the Department of Genetics and turned his attention to the study of bovine blood groups. Owen was fascinated by Lillie's observations,29 published in 1916, that 'demonstrated union of the circulatory systems between twin bovine embryos of the opposite sex.' Lillie had shown that hormones from a male fetus could enter the circulation of its female twin, producing developmental abnormalities of the reproductive system in the female twin. This 'modified' female twin is called a freemartin and is an early example illustrating the effect of hormones on sexual development.

"Owen examined 80 pairs of bovine twins for patterns of twinning, placental vascular anastomosis, and blood-group antigens.30 Finding that the majority of twin pairs displayed identical blood-group patterns, Owen reasoned that neither chance nor monozygotic twinning could explain the blood-group concordance. Rather, the exchange of erythroid progenitor cells through the same vascular anastomoses that carried Lillie's hormones was likely to be responsible. This remarkable insight, attributable more to Owen's powers of observation than to available technology, changed biology31 and introduced the notion of blood cell chimerism that was recognized by Dunsford and colleagues32 in their early description of a human blood-group chimera.   

"At the tissue level, chimerism can occur with solid-organ transplantation or, in the research setting, when a portion of an animal embryo is grafted to another species during the early stages of development. * * *


(B) Twin Pregnancy Types. New York-Presbyterian Hospital, undated.
https://www.nyp.org/healthlibrary/multimedia/twin-pregnancy-types
(Identical twins share one placenta, whereas fraternal twins each has its own placenta)
(C) Owen RD (University of Wisconsin), Immunogenetic Consequences of Vascular Anastomoses Between Bovine Twins. Science, 102: 400 (1945; second and last page, p 401, locked behind paywall)
https://www.science.org/doi/abs/10.1126/science.102.2651.400
("Estimates of the frequency identical as compared with fraternal twinning indicate that the former is relatively rare in cattle.4 Tests for inherited cellular antigens in the bloods of more than eighty pairs of bovine twins show, however, that in the majority of these pairs the twins have identical blood types. Identity of blood types between full sibs not twins is infrequent, as might be expected")
(D) Jacobsen DP, Fjeldstad HE, Olsen MB, Sugulle M, and Staff AC (Staff is last name; all authors from Norway), Microchimerism and Pregnancy Complications with Placental Dysfunction. Seminars in Immunopathology, 47: 21 (2025; click icon on right margin for free access)
https://pubmed.ncbi.nlm.nih.gov/40067448/
(Introduction: Microchimerism "arises naturally during gestation, when bi-directional transfer of cells across the placental barrier gives rise to fetal microchimerism in maternal systems and maternal microchimerism in fetal systems [2]. Some of these migrating cells have the ability to proliferate and differentiate within the host and have been observed decades after parturition. In women, cells possessing a Y-chromosome, of presumed fetal origin, have been detected in peripheral blood 27 years postpartum [1] and in the heart 24 years postpartum [3], exemplifying persistent fetal microchimerism in the mother. * * * Maternal and fetal microchimerism are found across mammalian species")
(E) Alexis Darby, The Case of Lydia Fairchild and Her Chimerism (2002). Embryo Project Encyclopedia, Arizona State University, June 1, 2021.
https://://embryo.asu.edu/pages/case-lydia-fairchild-and-her-chimerism-2002
(ii) Jacques Miller
https://en.wikipedia.org/wiki/Jacques_Miller
(born in 1931 in Nice, France; birth name Jacques Francis Albert Pierre Meunier; "grew up in France, Switzerland and China, mostly in Shanghai [where his father worked for an international bank]. After the outbreak of World War II, in anticipation of Japan's entry into the war, his family moved in 1941 to Sydney, Australia, and changed their last name to 'Miller.' * * * Miller studied medicine at the University of Sydney * * * He was accepted to the Chester Beatty Research Institute of Cancer Research [renamed after Alfred Chester Beatty, an American mining magnate who gave money to the Institute] (part of the Institute of Cancer Research, London) and as a PhD student at the University of London.[2]"/ became Australian in the process)
(A) His family changed last name not because they were Jewish, but because their last name is French word for miller and they now chose to live in Australia, an English-speaking country.
(B) French-English dictionary:
* meunier (noun masculine): "miller"
https://en.wiktionary.org/wiki/meunier
   ^ This word and French noun masculine moulin mill both descended from Latin noun neuter molīnum mill.
   https://en.wiktionary.org/wiki/moulin

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(c) "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 ([A]uto[I]mmune  [RE]gulator) gene by two consortia, one led  by Leena Peltonen [female; Finnish; husband was Aarno Palotie (thus en.wikipedia.org has a page for Leena Peltonen-Palotie; died in 2010 at 57 of bone cancer, osteosarcoma] (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 polyendocrinopathy candidiasis-ectodermal dystrophy (APECED) – collected by the [male] Finnish paediatrician Jaakko Perheentupa (Perheentupa 1996), and the other by the team of Nobuyoshi Shimizu [清水 信義; PhD 名古屋大学; professor 慶應義塾大学 医学部] (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). 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 self reactive 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"
(i) All of these references are locked behind paywall. But it is all right. AIRE role is still under study.
(ii) The following two were from Diane Mathis laboratory in Harvard Medical School.
(A) Thymic Epithelial Cells Co-Opt Lineage-Defining Transcription Factors to Eliminate Autoreactive T Cells. Cell, 185: 2542 (2022)
https://pmc.ncbi.nlm.nih.gov/articles/PMC9469465/
(Introduction: "Following T cell receptor (TCR) formation, immature T cells are first positively selected for self-major histocompatibility complex (MHC) recognition by cortical thymic epithelial cells (cTECs), then negatively selected for self-antigen reactivity by medullary thymic epithelial cells (mTECs) and other antigen-presenting cells (APCs). * * * Nearly two decades ago, the transcription factor (TF) Aire was shown to be an important driver of PTA expression: null mutations in Aire impair the expression of a large repertoire of ectopic transcripts in mTECs, and autoimmunity against Aire-dependent antigens subsequently develops in mice and humans (Aaltonen et al., 1997; Nagamine et al., 1997; Anderson et al., 2002)" )
(B) Thymic Mimetic Cells: Ontogeny as Immunology. Annual Review of Cell and Developmental Biology, 40: 283 (2024)
https://pmc.ncbi.nlm.nih.gov/articles/PMC11446667/

two consecutive paragraphs in INtroduction:

"Medullary thymic epithelial cells (mTECs) play a unique role in thymic tolerance by expressing the great majority of self-antigens ectopically within the thymus [reviewed in (Klein et al 2014)]. This includes ubiquitous antigens, such as actin or tubulin, as well as antigens whose expression is normally quite restricted to just one or a few tissues, such as insulin, mucins or myelin. Collectively, the antigens within the second class are known as peripheral-tissue antigens (PTAs). PTA expression by mTECs 'previews' the peripheral self to maturing T cells while they are still in the thymus, allowing for the deletion or diversion of self-reactive cells before they can cause harm.

"How a single cell type, the mTEC, manages to express so many self-antigens, many of whose expression is normally tightly controlled within particular cell types in the periphery, has been a source of longstanding intrigue. Two decades ago, a transcriptional regulator called Autoimmune regulator (Aire) was shown to play an important role, as its ablation diminishes expression of a large repertoire of PTAs within mTECs, and mice and humans with Aire/AIRE [Aire is mouse protein; AIRE is human protein] mutations develop autoimmunity against Aire-induced self-antigens (Anderson et al 2002, Finnish-German APECED Consortium 1997, Nagamine et al 1997). Subsequent mechanistic studies found that Aire acts 'stochastically,' 'probabilistically' or 'quasi-randomly' within individual cells to induce diverse and disparate genes * * *


At the bottom of this series of posting, there is "还有一些帖子被系统自动隐藏，点此展开." You need tio click to read the last two postings (altogether five) in the series.

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