Key Immunology Mouse Models in History

Key Immunology Mouse Models in History While the field of immunology has origins that date back to the 1500s, the field gained significant ground with the expanded use of mouse model systems. Fundamental discoveries elucidated in mouse models over the past 50 years are beginning to yield major breakthrough treatments for the most sinister human diseases, including inflammatory bowel disease, neurodegeneration, and cancer.

The immunologist's major professional association, the American Association of Immunology, is committed to highlighting these significant historical discoveries and connecting them with the modern advances they support.

Pillars of Immunology

The American Association of Immunology publishes the highly-regarded Journal of Immunology, where editors curated a tremendously popular series of landmark papers in their Pillars of Immunology collection. The manuscripts are accompanied by commentary from various immunology luminaries.

The milestone achievements of the most recognizable immunologists include the works of Doherty, Weigert, Marrack, Janeway, Allison, Rajewsky, and Flavell (to name only a few). Their work is part of the fabric that connects the fundamentals of immunology throughout history, and the "Pillars" series compiles it into a richly contextual quilt. Not coincidentally, many of the significant advances in the field of immunology are tied to the genomic revolution and the first uses of in vivo loss of function (i.e. Knockout Technology) studies in mice.

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Bevan on Immunology Mouse Models

One such "Pillars" commentary focused on the contributions of genetically engineered mouse models to the field of immunology. Michael Bevan's article, titled The Earliest Knockouts1, highlights the historical significance of mouse knockout models with mutations in the beta 2 microglobulin (B2M) gene, a critical component of the Major Histocompatibility Complex (MHC) class I protein complex.

His article centers on two papers, published in 1990 by the Jaenisch lab at the Whitehead Institute of MIT and the Smithies Lab at the University of North Carolina2,3. Bevan (himself, a legend in the field of T cell biology, is an author of 5 "Pillars" papers) provides a historical perspective on how these models influenced the field, including the work in his own lab seeking to define the mechanisms of thymic T cell selection (Bevan and Hogquist's 1994 contribution to thymic T cell selection is featured prominently in another Pillars article4).

Bevan also cites the B2M knockout models as a major factor influencing our understanding of NK (Natural Killer) cell lineage commitment and function, and how B2M knockouts supported Albert Bendelac's classic paper5 describing a subset of B2M dependent CD4+ T cells, a subset later defined as Natural Killer T cells.

These seminal papers and the subsequent research they influenced ushered in a new era of experimentation using mouse models with targeted gene mutations, conditional gene modifications, and transgenic gene expression. The B2M knockout stands out for its historical significance and the major discoveries it led to, but also because it signified the use of genetically engineered mouse models in immunology is here to stay.

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1. Bevan MJ. The earliest knockouts. J Immunol. 2010 May 1;184(9):4585-6. doi: 10.4049/jimmunol.1090023. PubMed PMID: 20410494; PubMed Central PMCID:PMC2982188.
2. Koller BH, Marrack P, Kappler JW, Smithies O. Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. Science. 1990 Jun 8;248(4960):1227-30. PubMed PMID: 2112266.
3. Zijlstra M, Bix M, Simister NE, Loring JM, Raulet DH, Jaenisch R. Beta2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature. 1990 Apr 19;344(6268):742-6. PubMed PMID: 2139497.
4. Hogquist KA, Jameson SC, Heath WR, Howard JL, Bevan MJ, Carbone FR. Pillars article: T cell receptor antagonist peptides induce positive selection. Cell. 1994. 76: 17-27. J Immunol. 2012 Mar 1;188(5):2046-56. PubMed PMID: 22345701.
5. Bendelac A, Killeen N, Littman DR, Schwartz RH. A subset of CD4+ thymocytes selected by MHC class I molecules. Science. 1994 Mar 25;263(5154):1774-8. PubMed PMID: 7907820.

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