Publisher Summary This chapter focuses on the important discovery that virus-specific cytotoxic T cells are dually specific for virus and for a self cell surface antigen encoded by the major histocompatibility complex (MHC). The initial work was carried out on the lymphocytic choriomeningitis virus system but it soon became evident that the same phenomenon applied to many other viruses. In addition, the same principle has been found to hold for other antigenic systems, such as trinitrophenyl coupled to cells, minor histocompatibility antigens, and the H-Y model. Graft rejection and the need for genetically homogeneous inbred mouse strains for cancer research led to the development of transplantation immunology and immunogenetics. The result is that the gene complex coding for major transplantation antigens is one of the better understood mammalian genetic regions. Cytotoxic T-cell specificity is comparable to serological specificity. Because quantification of specificity or cross-reactivity is difficult, and because of the technical limitations of these cytotoxic T-cell assays, results are interpreted with great reservation. MHC restriction reflects the fact that the effector function of T cells is determined by the kind of Self-H recognized together with the foreign antigen on cell surfaces: K and D are receptors for lytic signals, I determinants are receptors for cell differentiation signals that are delivered antigen-specifically by T cells.

MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness.

The study of human hematopoietic cells and the human immune system is hampered by the lack of a suitable experimental model. Experimental data are presented showing that human fetal liver hematopoietic cells, human fetal thymus, and human fetal lymph node support the differentiation of mature human T cells and B cells after engraftment into mice with genetically determined severe combined immunodeficiency. The resultant SCID-hu mice are found to have a transient wave of human CD4+ and CD8+ T cells and human IgG (immunoglobulin G) in the peripheral circulation. The functional status of the human immune system within this mouse model is not yet known.

https://science.sciencemag.org/content/sci/241/4873/1632.full.pdf

The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function.

http://www.biostat.umn.edu/~saonli/PUBH8445/Paper/DevlinRisch.pdf

A Comparison of Linkage Disequilibrium Measures for Fine-Scale Mapping

Biology of the Mouse Histocompatibility-2 Complex

Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response

The thymus determines the spectrum of the receptor specificities of differentiating T cells for self-H-2; however, the phenotypic expression of T cell's specificity for self plus virus is determined predominantly by the H-2 type of the antigen presenting cells of the peripheral lymphoreticular system Furthermore, virus specific helper T cells are essential for the generation of virus-specific cytotoxic T cells For cooperation between mature T cells and other lymphocytes to be functional in chimeras, thymic epithelial cells and lymphohemopoietic stem cells must share the I region; killer T-cell generation also requires in addition compatibility for at least one K or D region These conclusions derive from the following experiments: A leads to (A X B)F1 chimeric lymphocytes do produce virus-specific cytotoxic T-cell activity for infected A but not for infected B cells; when sensitized in an acutely irradiated and infected recipient (A X B)F1 these chimeric lymphocytes respond to both infected A and B Therefore the predominantly immunogenically infected cells of chimeras the radiosensitive and by donor stem cells replaced lymphoreticular cells In this adoptive priming model (KAIA/DB leads to KAIA/DC) chimeric lymphocytes could be sensitized in irradiated and infected F1 against KA and DC but not against infected DB targets In contrast KBIB/DA leads to KCIC/DA chimeras' lymphocytes could not be sensitized at all in appropriately irradiated and infected F1 recipients Thus these latter chimeras probably lack functional I-specific T helper cells that are essential for the generation of T killer cells against infected D compatible targets If T cells learn in the thymus to recognize H-21 or K, D markers that are not at least partially carried themselves in other cells of the lymphoreticular system immunological interactions will be impossible and this paradox situation results in phenotypic immune incompetence in vivo

https://rupress.org/jem/article-pdf/147/3/897/1089098/897.pdf

The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help.

H-2 dependent and virus-specific Ir genes regulate the generation of primary virus-specific K or D restricted cytotoxic T-cell responses in vivo. The following examples have been analyzed in some detail: first, Dk restricted responses to vaccinia in Sendai viruses are at least 30 times lower than the corresponding K-restricted responses irrespective of the H-2 haplotypes (k, b, d, dxs, dxq) of K and I regions; in contrast, LCMV infection generates high responses to Dk. These findings are consistent with but do not prove that this Ir gene maps to D. Second, Db restricted responses to vaccinia and Sendai viruses are high in strains possessing the Kq or KbIb, KbaIb haplotype, are very low in strains with Kk, and relatively low in mouse strains of the KdI-Ad haplotype; LCMV generates high Db restricted response in the presence of Kk. This Ir gene for the response to vaccinia and Sendai viruses maps to K since B10.BYR (KqIkdDb) is a responder and B10.A (2R) is a nonresponder (KkIkdDb). Third, virus and K or D allele specific nonresponsiveness is dominant with variable penetrance; in heterozygous mice the nonresponder Kk allele over-rides responsiveness normally found in KbDb or KqDb combinations. Fourth, when (responder X nonresponder)F1 lymphocytes are stimulated in an environment expressing vaccinia virus plus only a high responder Kb or Kq allelle and Db, response to vaccinia Db is high; in contrast when the same F1 cells are stimulated in an environment expressing the low responder allele Kk, response to vaccinia Db is low. Thus absence of Kk during immunization allows generation of high responsive Db restricted vaccinia specific cytotoxic T cells. The Dk dependent low response to vaccinia Dk can be explained by a preclusion rule or by failure of vaccinia to complex with Db; however the analysis of Kk dependent low response to vaccinia Db does not support these explanations or that self-tolerance is responsible for this Ir effect but is compatible with the interpretation that Kk vaccinia is immunodominant over Db vaccinia. These results are discussed with respect to (a) possible mechanisms of regulation by Ir genes and (b) H-2 polymorphism and HLA-disease association.

https://rupress.org/jem/article-pdf/148/2/592/1089296/592.pdf

Ir-genes in H-2 regulate generation of anti-viral cytotoxic T cells. Mapping to K or D and dominance of unresponsiveness.

Mice with t factors belonging to the same complementation group carry similar, if not identical, H–2 haplotypes although these factors were derived from widely separated geographical areas. This association between t and H–2 complexes suggests more than a casual relationship between the two complexes, at least at the population level.

/pdf/linkage-disequilibrium-between-h-2-and-t-complexes-in-2a77br4zqu.pdf

Linkage disequilibrium between H-2 and t complexes in chromosome 17 of the mouse.

The control of differentiation by the T complex.

C57BL/6 (H-2

 b
 ) mice and two mutants derived from this strain, B6.C-H-2

 ba
 (Hz1) andE6-H-2

 bd
 (M505), were studied in a number of functional tests, in vitro and in vivo, that assay for differences at theH-2 complex. All three strains give rise to reciprocal mixed lymphocyte reactivity (MLR) and cell-mediated lympholysis (CML) in vitro as well as graft-host reactivity (GVHR) and skin graft rejection in vivo. Analysis for cross-reactivity between these strains in CML revealed that the gained antigens in each mutant do not cross-react, and that Hz1 has lost an antigen shared by C57BL/6 and M505 strains. In addition, spleen cells from B10.A(4R) mice, which differ from theH-2

 b
 haplotype only at theK end of theH-2 complex, recognize a common antigen shared by all three strains tested. Provided that the mutations occurred in theH-2K

 b
 gene, these data indicate that a) there are at least three antigenic specificities coded for by theH-2K

 b
 gene(s) that serve as targets for receptors on thymus-derived (T) cells in CML; b) since C57BL/6 strain mice and the mutants are serologically indistinguishable on a qualitative basis, the antigens recognized by the receptors on T cells and by humoral H-2 antibody are nonidentical; and c) mutation in theH-2K

 b
 locus itself can give rise to allogeneic recognition phenomena such as MLR and GVHR.

Jan Klein

Papers

The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help.

Ir-genes in H-2 regulate generation of anti-viral cytotoxic T cells. Mapping to K or D and dominance of unresponsiveness.

Linkage disequilibrium between H-2 and t complexes in chromosome 17 of the mouse.

The control of differentiation by the T complex.

Analysis of H-2 mutants: Evidence for multiple CML target specificities controlled by the H-2K b gene