Inhibition of T-lymphocyte-mediated tumor-specific lysis by alloantisera directed against the H-2 serological specificities of the tumor

Abstract

After appropriate in vivo or in vitro immunization, cytotoxic T lymphocytes (CTL) are generated which efficiently kill cells bearing particular membrane antigens in common with the immunizing cell (reviewed in reference 1). Such CTL have been most thoroughly studied in mice, employing alloimmunization with cells differing at the major histocompatibility locus, H-2. in such cases, the predominant cell surface antigens recognized by the CTL appear to be the molecules carrying the serologically defined H-2 specificities, coded for by the K and D regions of the H-2 complex (2). In other syngeneic models of cell-mediated specific cytolysis, involving lymphocyte chariomeningitis (LCM) virus- or ectromelia virus-infected cells or TNP-modified lymphoid cells, thymus-derived cells also constitute the main effector cell type. The CTL generated in these latter systems function most efficiently when virus-infected or TNP-modified target cells share identitites at the H-2K or H-2D loci with the effector CTL and stimulator cells (3-5). Another set of experimental systems in which CTL are generated and play a significant biological role is that of immunity to tumor-associated antigens (TAA) (6). The nature of the TAA which the CTL recognize is only beginning to be understood. Several recent reports indicated the existence of physiochemical and/or antigenic relationships between TAA and H-2 antigens (7,8). These relationships, together with the genetic restrictions cited above in the generation of CTL involving products of the H-2K or H-2D loci suggested the possibility that in certain tumor systems, the TAA which are able to most effectively stimulate CTL responses might be structurally similar to, or linked with, the H-2K or H- 2D molecules on the tumor surface. It has been previously demonstrated in allogenic models that antisera specific for the appropriate H-2K or H-2D products present on a target cell could specifically block CTL-mediated lysis (1,9). This report demonstrates that certain anti-H-2 alloantisera specific for the target tumor cells can block lysis of those target cells mediated by syngeneic tumor-specific CTL effector cells.

Exclusive involvement of H-2D(b) or H-2K(d) product in the interaction between T-killer lymphocytes and syngeneic H-2(b) or H-2(d) viral lymphomas

“…The same phenomenon exists in the interaction between T-killer lymphocytes and syngeneic virusinduced tumor cells. This has been demonstrated both by immunization with oncogenic viruses (5)(6)(7)(8) and by grafl~ of syngeneic virus producer lymphoma cells (9)(10)(11). In murine sarcoma virus (MSV) tumors and in Friend virus (FLV) leukemias, such H-2 restrictions of CTL activity have been shown to occur during both primary in vivo response (5,6,9) and secondary in vitro CTL restimulation (12).…”

“…Though the exact role of H-2 directed molecules in the anti-MSV and anti-FLV reactions by syngeneic CTL is unknown, the hypothesis that the reactions are directed against altered self specificities as in other systems (1-4) appears more probable than the one requiring a double contact and sometimes designated as the intimacy theory (5,9,10,13). In most systems both Ho2D and H-2K have been implicated (1-4) but a predominant role of H-2K in vaccinia viral infection (14) and of H-2D in other systems (11,(15)(16)(17)(18)(19) including tumor antigens (11) has been noted.…”

Nature of the antigenic complex recognized by T lymphocytes II. T-cell activation by direct modification of macrophage histocompatibility antigens.

“…Bevan (14) has shown that mouse cytotoxic T cells directed against minor alloantigens must share the same allele at either the H-2K or H-2D locus with the target cell. Similarly, several other investigators (15)(16)(17) have dem-nstrated an association between MHC antigens and tumor-specific transplantation antigens. Although the chemical basis for these molecular interactions is as yet unknown, it is not too surprising that a similar process may be mediated by/-region antigens on other MHC antigens.…”

Natural cytotoxicity of haemopoietic cell populations against murine lymphoid tumours

“…It is unlikely that histocompatibility antigens themselves are involved in the antigenic site, as has been suggested for TAAs in other systems (Germain, Dorf and Benacerraf, 1975;Schrader and Edelman, 1976) since 51Cr-labelled tumour target cells allogeneic to the NK cells are readily lysed (Zarling et al, 1975;Kiessling et al, 1975a) and unlabelled allogeneic tumour cells can also successfully compete in cellular competitive-inhibibition assays with 51Cr-labelled tumour cells (Zarling et al, 1975;Kiessling et al, 1975a). Since normal lymphoid cells do not inhibit in such assays it has been inferred that normal tissue antigens are not involved (Zarling et al, 1975).…”

“…It is unlikely that histocompatibility antigens themselves are involved in the antigenic site, as has been suggested for TAAs in other systems (Germain, Dorf and Benacerraf, 1975;Schrader and Edelman, 1976) (Zarling et al, 1975;Kiessling et al, 1975a). Since normal lymphoid cells do not inhibit in such assays it has been inferred that normal tissue antigens are not involved (Zarling et al, 1975).…”