Genetic control of cytolytic t-lymphocyte responses. II. The role of the host genotype in parental leads to F1 radiation chimeras in the control of the specificity of cytolytic T-lymphocyte responses to trinitrophenyl-modified syngeneic cells.
01 Aug 1978-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 148, Iss: 2, pp 352-359
TL;DR: It is demonstrated that the host environment where T cells differentiate influences the specificity of the primary cytolytic T-lymphocyte (CTL) response to TNP-modified syngeneic antigens.
Abstract: Bone marrow cells from C3H (H-2k) mice, a strain that does not exhibit cross-reactive lysis of trinitrophenyl (TNP)-modified allogeneic targets, were allowed to mature in heavily irradiated (B6 times C3H)F1 (H-2b/k) recipients, an F1 hybrid that does demonstrate cross-reactive lysis. Spleen cells from these chimeric mice were removed after 3-4 mo and by H-2 typing shown to be of C3H origin. These cells were found to be tolerant to B6 alloantigens by mixed lymphocyte reaction and cell-mediated cytotoxicity and, when stimulated in vitro with TNP-modified syngeneic cells, now cross-reactively lysed TNP-modified allogeneic targets. These studies demonstrate that the host environment where T cells differentiate influences the specificity of the primary cytolytic T-lymphocyte (CTL) response to TNP-modified syngeneic antigens.
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TL;DR: Experiments demonstrate that even at the earliest time CTL effectors of donor origin from the thymuses of chimeras can be studied, their self- receptor repertoire has already been restricted to recognition of host MHC determinants.
Abstract: In this study the cytotoxic T lymphocyte (CTL) recognition pattern of thymocytes from recently reconstituted parent leads to F1 and F1 leads to parent radiation bone marrow chimeras was investigated. Chimeric thymocytes were entirely of donor origin approximately 4 wk after irradiation and reconstitution but were not capable of autonomously generating either alloreactive or trinitrophenyl (TNP)-modified-self-reactive CTL responses. However, in the presence of interleukin-2 (I1-2), the the putative T helper cell product, CTL could be generated in vitro by thymocytes from recently reconstituted chimeras. Experiments with thymocytes from A leads to A X B and A X B leads to A chimeras revealed the following: (a) thymocytes from both types of chimeras were nonreactive to either A or B parental major-histocompatibility complex (MHC) determinants even though they were alloreactive to third-party stimulator cells; and (b) thymocytes from these chimeras were restricted to the recognition of TNP in association with MHC determinants syngeneic to the chimeric host. Thus, these experiments demonstrate that even at the earliest time CTL effectors of donor origin from the thymuses of chimeras can be studied, their self-receptor repertoire has already been restricted to recognition of host MHC determinants. These results support the concept that the host environment influences the self-recognition capacity of T cells at the pre- or intrathymic stage of differentiation.
26 citations
TL;DR: This chapter considers some of these investigations and offers certain models that elucidate the role of the histocompatibility gene products in T-cell activation and the effects these genes may have in determining resistance to certain tumors.
Abstract: Publisher Summary This chapter provides a better understanding of the function of histocompatibility gene products and of the advantages of polymorphism of the loci that code for these products. The chapter considers some of these investigations and offers certain models that elucidate the role of the histocompatibility gene products in T-cell activation. The effects these genes may have in determining resistance to certain tumors are discussed in the chapter. Genes of the major histocompatibility complex (MHC) exert a profound influence on T lymphocytes. The MHC-linked Ir genes control T-cell activities and T-cell-dependent functions, and the reactivities of various T-cell subsets are restricted by distinct MHC genes. I-region gene products govern the immune responses of T H and T D cells to antigens presented by macrophages and B cells. H-2K and H-2D gene products influence the response of Tc cells, which play an essential role in resistance to virus infections. The exact manner by which the MHC produces such effects is not known, but several possible mechanisms are discussed in this chapter.
26 citations
TL;DR: This chapter discusses some of the key features of cell-mediated cytotoxic immune responses to syngeneic tumors and reviews the most frequently used murine tumors.
Abstract: Publisher Summary An interpretation of the function of major histocompatibility complex (MHC) in cytotoxic T cell responses requires making certain assumptions, which, because of the lack of experimental data, are often based on intuition. This chapter discusses some specific aspects of the role of MHC in cytotoxic T cell responses. It also summarizes the expression of T cell-mediated responses to alloantigens. It also focuses on H-2-restricted cytotoxic T lymphocytes (CTL) responses and discusses the influence of the MHC on cytotoxic T cell specificity and CTL responsiveness against foreign antigens. T cell responses to alloantigens mirror all the functional activities seen in H-2-restricted T cell responses to foreign antigens. Because of the high frequency of T cells for a given alloantigen, it is postulated that the T cell receptor repertoire is driven by H-2 antigens, as originally suggested for B cells. The high frequency of T cells for alloantigens reflects the degree of relatedness of alloantigens with the host's own H-2 antigens. Experimental tumors are grouped according to their mode of induction. The chapter discusses some of the key features of cell-mediated cytotoxic immune responses to syngeneic tumors and reviews the most frequently used murine tumors.
25 citations
TL;DR: The requirement of activated CTL for antigen to proliferate provides an explanation for how specific CTL can be selectively enriched in MLC by specific antigen stimulation and shows that factor-dependent CTL lines must recognize their specific antigen to proliferation, even in the presence of exogenous factors.
Abstract: We investigated the antigenic requirements for restimulation of H-2- restricted cytolytic T lymphocytes (CTL) in vitro to determine whether H-2 I region-restricted helper T cells are required in these responses. In one set of experiments, we studied the in vitro response of (responder x nonresponder)F(1) female T cells to the male antigen H-Y. We chose to examine this response because it has been suggested that the defect in nonresponder strains is a failure of helper T cells to recognize H-Y in association with nonresponder I region determinants. However, we find that nonresponder male stimulator cells are as effective as F(1) male stimulator cells at inducing H-Y-specific CTL responses. This finding calls into question reports that secondary CTL responses to H-Y are dependent upon the activation of H-Y- specific helper T cells restricted to responder type I region determinants. In a second set of experiments, we examined the requirements for restimulation of H-2-restricted T cells specific for minor-histocompatibility antigens from long-term mixed lymphocyte cultures. These cultures were established by repeatedly restimulating cultures of specific T cells with H- 2-matched stimulator cells expressing foreign minor histocompatibility antigens. We found that H-2D-restricted T ceils, including CTL, could be restimulated with cells that were matched with the responding cells at only the D region genes. This response did not appear to result from positive allogeneic effects or from antigen processing and “representation” by responder type APC that might contaminate the cultures. Thus, we find no evidence for a requirement for I region-restricted helper T cells in these CTL responses. However, helper T cells are required because we find that CTL lines derived by limit-dilution cloning from these long-term MLC are absolutely dependent upon exogenous helper factors for growth. The most simple interpretation of these results is that the helper cells are restricted to H-2 antigens other than I region antigens or to antigens that code outside of the H-2 complex. Finally, we show that factor-dependent CTL lines must recognize their specific antigen to proliferate, even in the presence of exogenous factors. The requirement of activated CTL for antigen to proliferate provides an explanation for how specific CTL can be selectively enriched in MLC by specific antigen stimulation. Furthermore, it is at variance with reports that memory CTL or activated CTL require only interleukin 2 for restimulation.
21 citations
TL;DR: It is possible that at least part of the phenomenology associated with the F(l) {arrow} parent radiation chimeras reflects deletion of repertoire in the context of H-2 antigens present during thymocyte ontogeny on other than radiation-resistant thymic epithelium.
Abstract: Negatively selected H-2K(b)D(b) TDL can be induced to respond strongly to vaccinia virus presented in the context of both H-2K(k) and H-2D(b) when stimulated in irradiated H-2K(k)D(b) recipients. Addition of excess (H- 2K(k)D(b) x H-2K(b)D(b))F1 TDL, which are low responders to H-2D(b)-vaccinia virus, does not obviously suppress the reactivity pattern of the H-2K(b)D(b) T cells. However, lymphocytes from chimeras made by reconstituting H- 2K(b)D(b) mice with (H-2K(k)D(k) × H-2K(b)D(b))F(l) bone marrow cells make little, if any, cytotoxic T-cell response to vaccinia virus when sensitized in H-2K(k)D(b) recipients. We have thus documented one instance where the responder phenotype of T ceils from an F(l) {arrow} parent chimera is not equivalent to that associated with the H-2 type of the parental thymus. Lymphocytes from both the chimera and the H-2K(b)D(b) parent (after negative selection) are tolerant to the H-2K(k) and I-A(k) alloantigens encountered in the recipient, but the chimera T cells are also defective in their response to a neoantigen (vaccinia virus) presented in the context of H-2K(k) which the parental T cells invariably recognize. It is thus possible that at least part of the phenomenology associated with the F(l) {arrow} parent radiation chimeras reflects deletion of repertoire in the context of H-2 antigens present during thymocyte ontogeny on other than radiation-resistant thymic epithelium.
21 citations