Genetic linkage of the cytolytic T lymphocyte repertoire and immunoglobulin heavy chain genes.

Abstract

A variety of experimental approaches have been used to study genetic determination of the T cell receptor. Evidence that anti-idiotypic antibodies prepared against immunoglobulin bind T cells or T cell products that demonstrate the appropriate antigen specificity suggests genetic linkage between T and B cell idiotypes (1-5). In contrast, T lymphocytes that demonstrate a requirement for recognition of molecules encoded by the major histocompatibility complex (MHC) as well as foreign antigen, such as proliferative or cytolytic T lymphocytes (CTL), do not appear to express idiotypes that predominate in antibody responses (4,(6)(7)(8)). An alternative strategy that has been successfully applied to the study of genetic control of allospecific T cell receptors has been to obtain anti-idiotypic antisera by direct immunization with allospecific T cells (2, 4). Using such antisera, Krammer and Eichmann (9) demonstrated that both the MHC and immunoglobulin heavy chain genes (Igh) participate in genetic determination of murine T cell idiotypes. In a similar study in the rat, Binz and co-workers (10) found that idiotype expression was linked to Igh but not to MHC. Also in the rat, but using presumptive anti-receptor T cells rather than anti-receptor antibodies, Bellgrau and Wilson (11) concluded that allospecific T cell receptors displayed little if any polymorphism and thus found no evidence for linkage to polymorphic loci such as MHC or Igh. In view of the difficulties reported in obtaining and characterizing anti-receptor reagents (6-11) as well as the ambiguities inherent in such an indirect approach (12, 13), a direct method was sought that could be applied to study genetic determination of the T cell repertoire.Recent advances in techniques of T cell cloning have permitted analysis of the CTL receptor repertoire by studying the fine specificity of monoclonal CTL. As previously reported (14), this approach has supplied a detailed description of the H-2Kb-specific receptor repertoire by identifying and distinguishing each of a large number of H-2Kb-specific clones on the basis of their reactivity against a panel of H-2K b mutants. This has proven to be a useful alternative to anti-idiotypic antisera for studying genetic control of the T cell receptor repertoire. In view of the great diversity of receptor specificities within the H-2Kb-specific repertoire, the success of repertoire analysis as a tool for genetic studies is attributable to the existence, within a given inbred strain, of one or several receptor specificities that recur at an unusually high frequency. In a previous study (15,16) that compared the specificity repertoire of two MHC congenic strains, B10.D2 and B10.BR, it was found that each strain expressed different recurrent specificities. Therefore, recurrent specificities are useful phenotypic markers. In studies designed to probe the mechanism responsible for the * Supported by grants AI 15710 and CA 25803 from the U. S. Public Health Service. 294J. Exp. MED.

Suppressor T-cell factor(s) display an altered pattern of Igh (immunoglobulin heavy chain locus) genetic restriction when developed in an Igh-congeneic host.

“…In addition, Igh-controlled specificities have been reported to function as restriction elements in various cellular-interaction pathways (7,8). Moreover, the role of Igh genes and their products in the development of the T-cell repertoire has also been suggested by the observation that Igh-linked genes control the crossreactive patterns of alloreactive cytotoxic T cells (CTLs) (9). These findings were generally interpreted to indicate that T and B cells may use identical Ig heavy chain variable-region (VH) genes to encode their antigen-specific receptors.…”

Use of somatic cell genetics to study chromosomes contributing to antigen plus I recognition by T cell hybridomas.

“…Hybridomas Derived from Fusions to Rb (16,17)7 T Cell Blasts. Five Rb(16.17)7 mice were primed with KLH; 7 d later, cells from draining lymph nodes were cultured with KLH followed by IL-2, and fused to FS6-14.13.AG2.1 as described in Materials and Methods.…”

“…Discussion Considerable interest centers on mapping genes that code T cell receptor(s) for Ag/ L In fact finding the chromosomes that do not bear the receptor(s) is probably as significant as finding the ones that do, depending on which these turn out to be. Various theoretical and experimental considerations have suggested that in the mouse genes controlling Ag/I receptors should be found on chromosomes bearing immunoglobulin heavy chain genes and/or MHC genes, i.e., chromosomes 12 and 17, respectively (6)(7)(8)(9)(10)(11)(12)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Since on occasion Ag-binding T cell products have been shown to bear immunoglobulin idiotypes thought to be controlled by a combination of immunoglobulin light and heavy chains, chromosomes bearing light chain genes, i.e., chromosomes 6 and 16 (21,22), may also be implicated, although this is apparently not necessarily true (35).…”

Genetic Determination of the Cytolytic T Lymphocyte Receptor Repertoire

“…In order simultaneously to screen the effect of numerous polymorphic genes on T repertoire expression, we compared the H-2Kb-specific responses of two strains which share both MHC and Igh yet are otherwise of independent origin, CB-20 and B 1O.D2 [4]. Both strains are H-2d, Igh b yet CB-20 is of BALB/c origin and therefore broadly differs from B 10.D2.…”

“…This entails antigenic stimulation of a large number of cn clones under limiting dilution culture conditions, followed by identification of the receptor specificity of each clone by fine specificity analysis [1][2][3][4]. The murine H-2Kb antigen is uniquely suited to such an approach owing to the availability of a large number of H-2Kb mutants that provide a panel of heterologous targets required for fine specificity analysis.…”