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.

CELL membrane structures controlled by genes in the major histocompatibility complex (H–2 in mice) are involved in most immune interactions between T lymphocytes and other cells1. Cytotoxic T lymphocytes (CTL) immunised against viruses2, haptens3, minor histocompatibility antigens4 or tumour antigens5, are specific for self H–2 antigens as well as for the foreign antigen. But CTL are not restricted to recognising antigens in combination with only self H–2. H–2d homozygous CTL which have matured in an irradiated H–2d/H–2k host can respond to antigen plus H–2k in addition to antigen plus H–2d (refs 6–8). It is not known whether the H–2 environment in which T cells mature influences their range of specificity, that is, whether CTL from a normal mouse can respond quantitatively as well to antigen plus foreign H–2 as they do to antigen plus self H–2. These experiments were designed to test this influence. The results suggest that host H–2 antigens do exert an effect on the specificity of T-cell responses.

In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells

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In a radiation chimaera, host H–2 antigens determine immune responsiveness of donor cytotoxic cells

Contemporary Topics in Immunobiology

Publisher Summary This chapter opens up with a detailed analysis of the early experiments of these scientists, culminating in the discovery by McDevitt that these genes were linked to the major histocompatibility complex (MHC). One of the major unifying threads in cellular immunology that ended in the identification of MHC-encoded molecules as the Ir gene products and the merging of the two phenomena: Ir gene control and MHC restriction (the requirement for T cells to recognize an MHC-encoded molecule in addition to the antigen in order to become activated). The recent developments in cellular and molecular cloning have moved the problem of Ir gene function to the biochemical level. Ir genes are genetically linked to the MHC. A formal proof of the genetic linkage of Ir-genes to the MHC was performed using the segregating population in a backcross to the low responder parent.

Immune Response(Ir)Genes of the Murine Major Histocompatibility Complex

MICE immunised with infectious lymphocytic choriomeningitis virus (LCMV) produce T lymphocytes which can kill LCMV-infected target cells in vitro only if the killer and target cells are syngeneic at the H–2K and/or H–2D loci1,2. We now report analogous results obtained in studies of the immune response of syngeneic or semi-syngeneic mice to cultured cell lines derived from tumours induced in vivo by Friend murine erythroleukaemia virus (FV). Our studies further indicate that the H–2 type of the cells used for immunisation is also a decisive factor in the specificity of the killer cells generated.

T-lymphocyte response to Friend virus-induced tumour cell lines in mice of strains congenic at H–2

. At least two genes which influence susceptibility to viral leukemogenesis map at closely linked but separate locations within the H-2 region of chromosome 17 in the mouse. Experiments bearing upon their apparently different mechanisms of action are summarized. One gene, associated with the K or I segments of H-2 , appears to operate by influencing the capacity of the host to mount an immune response to virus-specified leukemia cell antigens. Another gene, associated with the D segment of H-2 , may influence the likelihood of the occurrence of clones of tumor cells no longer expressing certain viral antigens and therefore resistant to immunologic attack by the host.

Mechanisms of the H-2 effect on viral leukemogenesis.

https://www.cell.com/cell/pdf/0092-8674(78)90135-6.pdf

Herbert A. Freedman

Papers

T-lymphocyte response to Friend virus-induced tumour cell lines in mice of strains congenic at H–2

Mechanisms of the H-2 effect on viral leukemogenesis.

Variations in viral gene expression in friend virus-transformed cell lines congenic with respect to the H-2 locus

Mechanisms of the h-2 effect on viral leukemogenesis