The results of this study provide compelling evidence for the existence of the gene or genes controlling optimal T-B-cell cooperative interactions in the designated I region of the H-2 gene complex. Previously, we have speculated that the relevant gene(s) involved may well be located in this region based on several observations from our earlier work in this area (3, 5, 6). Thus, in the preceding paper, we showed that T and B cells from B10.BR and A strain mice developed effective cooperative interactions in vitro to DNP-KLH in a system identical to the one reported herein. Since these mice differ for genes in the S and D regions of H-2 but are identical for K and I region genes, we were able to localize the critical genes to the K-end of H-2.
Suppressor factor derived from three different murine T cell hybridomas were characterized . They specifically inhibited 4-hydroxy-3-nitrophenyl acetyl cutaneous sensitivity responses. The factors bind antigen and bear I-J and idiotypic determinants, but lack conventional immunoglobulin constant-region determinants. The factors function during the induction phase of the immune response, by inducing a second population of suppressor cells (Ts(e)). Suppressor factor can inhibit both cellular and plaque-forming cell responses in appropriate strains of mice. These hybridoma suppressor factors directly suppress strains of mice that are Igh-V homologous with the strain producing the factor. Thus, there is an apparent Igh-V restriction in the activity of these factors. However, this is a pseudogenetic restriction because these factors generate second order suppressor cells (Ts(e)) in Igh-incompatible mice, but in order to express the suppressive activity, the cells must be adoptively transferred into recipients that are Igh compatible with the strain producing the suppressor factor. Finally, it was shown that the factor-induced Ts(e) population is under an apparent dual genetic restriction. Thus, Igh and H-2 homology is required in order for the Ts(e) population to express its suppressive activity.
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.
The role of the products of the K and D loci of the H-2 complex as target antigens for cytotoxic T l3-alanylglycylglycyl) modified syngeneic cells (2-14). The interaction of non-H-2 or minor histocompatibility antigens with products of the K and D loci to form target antigens has also been reported (15). Moreover, in recent experiments from this laboratory, we have shown in a syngeneic system that the activity of cytolytic T cells specific for tumor-associated antigens is inhibited by alloantisera directed against the H-2Dd locus (16).The model system described by Shearer (9) makes possible the development of immunological probes to assess, on a functional and molecular level, the role of the H-2 complex in cytolytic T cell-target interaction. This paper describes results obtained using specific alloantisera to investigate the role of the D and K gene products in T cell cytolysis of trinitrophenyl (Tnp)-modified syngeneic targets. The data presented show that such antibodies can specifically inhibit cytolysis when directed against the appropriate D or K target cell specificities, reveal that these T-lymphocyte may also be cytolytic for Tnp-conjugated allogeneic cells, and demonstrate that such crossreactive cytolysis is also regulated by the D and K loci, as shown by alloantisera inhibition. MATERIALS AND METHODSMice. All mice were between 6 and 12 weeks of age and were purchased from Jackson Laboratory, Bar Harbor, Maine.
Recent advances in cell hybridization techniques have permitted the fusion of functional T cell subpopulations with tumor cells to yield stable T cell hybridomas (1-9). Such hybrids immortalize the biological activity of an individual cell and permit analysis of monoclonal T cell-derived helper (5) and suppression factors (2,4,6,9,10). The preparation of monoclonal T cell hybridomas and isolation of biologically active factors derived from monoclonal hybridoma lines can provide a means of dissecting interacting T cell subsets that exist within heterogeneous T cell populations. Such an approach permits a more precise understanding of the mechanism of T cell interactions.Immune suppression is one such T cell-mediated activity in which multiple T cell populations and soluble factors are required (11). Although initial characterization of the various suppressor T cell populations (Ts) 1 has been possible with heterogeneous Ts populations, it remains difficult to analyze the contributions of individual T cell subsets and to insure that a single subset instead of a mixture of subsets is being studied. Furthermore, the quantities of cells or factors obtained from conventional cell preparations are often insufficient for detailed analysis. Thus, the establishment of monoclonal T cell hybrids with specific suppressor function provides an ideal tool for the characterization of the distinct suppressor cell subsets, their products, and their interactions.Regulation of the immune response to the hapten 4-hydroxy-3-nitrophenyl acetyl (NP) has been extensively characterized (12-16). Previous studies using conventional analysis and monoclonal T cell hybridomas have revealed that in the NP suppressor cell pathway at least three distinct subsets of T cells are required for suppression (13,14). The first set of Ts, termed Tsx, are induced by antigen, bear idiotypic (Id +) receptors, and can function early in the immune response (10, 12). These Tsl cells, or a factor produced by these cells, can induce a second set of Ts, termed Ts2 (10, 13, * Supported by grants CA 14732 and AI 16677 from the National Institutes of Health and grant PCM 80-04573 from the National Science Foundation.L Abbreviations used in this paper: C, complement; CGAT, common idiotype on anti-GAT antibodies; CS, cutaneous sensitivity; DMSO, dimethyl sulfoxide; DNFB, 2,4 dinitro-l-fluorohenzene; HBSS, Hanks' balanced salt solution; KLH, keyhole limpet hemocyanin; NP, 4-hydroxy-3-nitrophenyl acetyl hapten; NP b, common idiotype on C57BL anti-NP antibodies; NP-O-Su, NP-O-succinimide ester; PBS, phosphatebuffered saline; RAMG, rabbit anti-mouse immunoglobulin; Ts~, Ts2, Tss, first-, second-, or third-order suppressor T cells, respectively; TsFI, TsF2, TsFa, suppressor factor derived from Tsl, Ts2, or Tss cells, respectively. 1838J. Exp. MED.
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