The concept that tissues transplanted between genetically dissimilar individuals are immunologically rejected is grounded in discoveries of pioneering mouse geneticists at the beginning of the 20th century. At that time, Mendel’s genetic laws had been recently rediscovered and William E. Castle at the Bussey Institute at Harvard focused on testing genetic principles in rodents and rabbits. Clarence C. Little, who would eventually found the Roscoe B. Jackson Memorial Laboratory, was one of his particularly precocious students and concentrated his studies on mice. His seminal contribution in collaborative studies with Ernest E. Tyzzer, also at Harvard, was to explain an inconsistency that challenged a basic premise of Mendel’s laws. Consistent with the laws operating in cancer, tumors transplanted to the originating mouse strain and to F1 hybrids grew progressively, indicating that tumor survival was a dominant trait. However, the problem was that the tumor would not survive in F2 progeny, which is inconsistent with simple Mendelian inheritance. Little and Tyzzer’s (1) fundamental impact was a genetic explanation for this inconsistency. They showed that the tumor did survive in a small number of F2 progeny. Their interpretation was that the rare survival of a tumor could be explained by the existence of several genes that, when genetically matched with the tumor, would permit tumor growth. This was the first inkling of complex genetic traits in mammals, a principle that we now realize governs virtually all common human genetic disorders.

George Snell’s entry into the genetics of tissue transplantation stemmed from his activities as editor of the book titled Biology of the Laboratory Mouse, compiled by the Staff of the Roscoe B. Jackson Memorial Laboratory in 1941 (2). At that time there were hints through the work of others that transplant survival and rejection were not limited to tumors but, instead, were general properties of heterologous or allogeneic tissues; the contribution of the immune response was unknown. Little contributed chapters on the genetics of tumor transplantation that engaged Snell’s interest and set the stage for his career-defining works.

In “Methods for the Study of Histocompatibility Genes” (3), Snell provided his conceptual groundwork for unraveling the genetics of histocompatibility (the term he introduced) while also establishing a method for creating the workhorses of mouse genetics, what we now refer to as congenic mouse strains. The complexity of the task was daunting. In that era, understanding of mammalian genetics was in its infancy. The mammalian genome was essentially dark matter punctuated by only 12 visual phenotypic markers for linkage analyses. All that was known regarding histocompatibility (H) genes consisted of minimal estimates of up to 14 H loci based solely on inferences from tumor survival patterns observed in mouse crosses. Snell proposed an ambitious and risky approach to genetically isolate each H locus by selection of the histocompatibility trait of resistance to an allogeneic tumor transplant in successive backcross/intercross generations. Selection of tumor-resistant progeny in each generation would purify the background genetics by 50% according to mathematical predictions of Haldane and Waddington (4), eventually resulting in “isogenic resistant” strains differing from the parental strain solely by the isolated H locus. This effort was made even more difficult because many of the strains Snell was developing were lost when the Roscoe B. Jackson Memorial Laboratory was destroyed by fire in 1947. In the Maine downeaster tradition, Snell was persistent and recreated several of the lost strains, many of which are still in use today. The fruits of Snell’s endeavors were H locus congenic mouse strains. Use of the strains validated Little and Tyzzer’s hypothesis of the complex genetics of histocompatibility; this must have been particularly rewarding to Snell, the archetypical geneticist. Incidentally, the strains permitted the genotype-to-phenotype correlations that led to our understandings of H-2, the mouse MHC, as well as what are now referred to as minor H loci.

H-2 proved to be the strongest barrier to rejection, the importance of which continues to reverberate. The intersection of H-2 with the immune response emerged partially from serendipity (H-2 was conveniently linked to the visual marker fused, which made it easy to track genetically), and a collaborative study with Peter Gorer showing that Gorer’s serologically defined Ag II was linked to fused (5). Maybe tumor rejection was caused by alloantigens that stimulated an immune response! These insights seeded the concept that self/non-self discrimination was under genetic control.

Then things got even more interesting. In two seminal publications, Snell (6) and Snell and Higgins (7) provided the first evidence that H-2 was unique among H loci: it was a much stronger barrier to rejection than the other H loci, it was unusually polymorphic, and it might be a gene complex. Snell’s H-2 congenic strains and his willingness to distribute them provided the central mouse tools for the next generation of immunologists and immunogeneticists to extract ever deeper immunological properties controlled by genes of the MHC and their genetic variants. These insights included intra–H-2 recombinants that led to the functional dissection of the MHC into immune response genes controlling CD4+ T cells (8, 9), CD8+ T cells (1013), and NK cells and their ligands (14), as well as Ag processing (15) and MHC restriction (1618) and its all-revealing structural explanations (19, 20). His H-2 congenic mouse strains also provided the first insights into the extraordinary polymorphism of genes within the MHC and the remarkable influence that MHC polymorphism exerts on virtually all infectious, inflammatory, and autoimmune disorders.

Whereas H-2 was the seminal contribution that led to Snell receiving a Nobel Prize in 1980, additional H congenic strains produced by his histogenic methods served other purposes. Minor H loci–congenic strains demonstrated that allelic variation in non-MHC–encoded proteins could result in barriers to transplantation and could be used productively to improve the success of allogeneic bone marrow transplantation for treatment of leukemia and lymphoma by exploiting the graft-versus-leukemia response (21). Their most significant contribution, however, was to help elucidate the underpinnings of self/non-self discrimination by T cells (22). Rammensee and colleagues (23) elegantly exploited minor H congenics to detect the response of CD8+ T cells to allelically variant minor H Ags and to prove the biochemical basis of MHC restriction: a complex comprised of processed endogenous peptides bound selectively to MHC class I proteins. Finally, the advent of T cell and DNA cloning techniques, unimagined by Snell, enabled the molecular identifications of several of his operationally identified minor H loci—H-3, H-4, H-7, and H-13—as genes encoding allelically variant self-peptides whose immunological visibility is dictated by their ability to bind MHC proteins (24, 25).

This Pillars of Immunology article lays out Snell’s course for probing the unknown with the tools at hand. Although elegant in its genetic logic and reasoning, I imagine that Snell was surprised that the approach worked as well it did, and was even more pleasantly surprised that his histogenetic approaches resulted in the discovery of mouse MHC. As important, at least from this author’s perspective, is his establishment of genetic approaches and mouse strains that enabled innumerable discoveries by others. Not bad for a “methods paper”!

I am highly indebted to Herbert C. Morse, III, for critical review of this commentary.

Abbreviation used in this article:

H

histocompatibility.

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The author has no financial conflicts of interest.