In irradiation chimeras, K or D regions of the chimeric host, not of the donor lymphocytes, determine immune responsiveness of antiviral cytotoxic T cells
01 Sep 1978-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 148, Iss: 3, pp 805-810
TL;DR: The results indicate that in chimeras, the Ir phenotype is independent of the donor T cell’s Ir genotype, and that thymic selection of a T cell ’s restriction specificity for a particular H-2 allele of the chimeric host also defines that T cell's/r phenotype.
Abstract: The H-2 haplotype of the chimeric host determines the responder phenotype of maturing T cells. Spleen cells of chimeric mice formed when (K(k) nonresponder to D(b) × K(b) responder to D(b) plus vaccinia)F(1) bone marrow cells were used to reconstitute K(b)D(b) (C57BL/6 D(b) responder) irradiated recipients generated high levels of D(b) plus vaccinia virus-specific cytotoxic T cells. The same stem cells used to reconstitute K(k)D(b) (B10.A (2R) D(b) nonresponder) irradiated recipients resulted in spleen cells that responded well to K plus vaccinia, but responsiveness to D(b) was low. A generally low response to D(k) plus vaccinia, which seems to be regulated by D(k), was confirmed in chimeras. Thus, K(d)D(d) (D(d) plus vaccinia responder) stem cells differentiating in a K(d)D(k) chimeric host failed to generate a measurable response to D(k) plus vaccinia. In contrast, stem cells from K(d)D(k) (D(k) plus vaccinia low responders) differentiating in a K(d)D(d) (K(d) and D(d) high responders to vaccinia) host do generate responsiveness to D(d) plus vaccinia. These results indicate that in chimeras, the Ir phenotype is independent of the donor T cell’s Ir genotype, and that thymic selection of a T cell’s restriction specificity for a particular H-2 allele of the chimeric host also defines that T cell’s/r phenotype.
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TL;DR: 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).
Abstract: 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.
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649 citations
TL;DR: It is found that removal of calcineurin activity from thymocytes results in inefficient ERK activation at the double-positive stage of thymocyte development, when selection occurs, and indicates that the developmental roles of calciningurin likely contribute to immunosuppression by calcineURin inhibitors.
220 citations
TL;DR: It is reported that injection of allogeneic stimulator cells plus a Lyt 1 T-cell-derived helper factor18,19, termed interleukin 2 allows lymphocytes of nu/nu mice to differentiate in vivo into alloreactive cytotoxic T lymphocytes (CTLs).
Abstract: T-cell immunocompetence and diversity are thought to be generated in the thymus1,2. This view is based on the findings that (1) T-cell ontogeny is thymus dependent3,4, (2) the major histocompatibility restrictions of T-cell interactions are phenotypically related to the H–2 type of the thymus5–9, and (3) the phenotypic manifestation of H–2-linked immune responsiveness parallels the restriction elements selected in thymus10–12. However, it is unclear whether pre-thymic cells programmed to develop into T cells do already express a receptor diversity, also whether pre-thymic cells have the potential to react against self-antigens, and whether the mechanism of self-tolerance is initiated in the thymus by either elimination or suppression of self-reactive clones. If it were possible to confer on pre-thymic cells antigen-specific effector functions, the impact of the thymus on the generation of T-cell diversity and function could be analysed in more detail. In mice, the nude mutation lacks a functioning thymus13,14; nu/nu mice possess a thymic rudiment which is epithelial in the embryo15 and a fibrous, cystic remnant in adult15,16; this remnant is not populated by lymphoid cells15–17. At present, the absence of immunocompetent T cells in nu/nu mice is explained by a lack of thymic differentiation and maturation of pre-thymic cells (reviewed in ref. 13). Here we report that injection of allogeneic stimulator cells plus a Lyt 1 T-cell-derived helper factor18,19, termed interleukin 2 (for the system of nomenclature, see ref. 20) allows lymphocytes of nu/nu mice to differentiate in vivo into alloreactive cytotoxic T lymphocytes (CTLs).
216 citations
References
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TL;DR: Adult thymectomized, irradiated and bone marrow reconstituted mice, transplanted with an irradiated thymus of A origin, generate virus-specific cytotoxic T cells specific for infected A targets but not for B targets; this result formally demonstrates the crucial role of thymic epithelial cells in the differentiation of anti-self-H-2 specificities of T cells.
Abstract: In the thymus, precursor T cells differentiate recognition structures for self that are specific for the H-2K, D, and I markers expressed by the thymic epithelium. Thus recognition of self-H-2 differentiates independently of the T cells H-2 type and independently of recognition of nonself antigen X. This is readily compatible with dual recognition by T cells but does not formally exclude a single recognition model. These conclusions derive from experiments with bone marrow and thymic chimeras. Irradiated mice reconstituted with bone marrow to form chimeras of (A X B)F1 leads to A type generate virus-specific cytotoxic T cells for infected targets A only. Therefore, the H-2 type of the host determines the H-2-restricted activity of killer T cells alone. In contrast, chimeras made by reconstituting irradiated A mice with adult spleen cells of (A X B)F1 origin generate virus-specific cytotoxic activity for infected A and B targets, suggesting that mature T cells do not change their self-specificity readily. (A X B)F1 leads to (A X C)F1 and (KAIA/DC) leads to (KAIA/DB) irradiation bone marrow chimeras responded against infected A but not B or C targets. This suggests that cytotoxicity is not generated against DC because it is abscent from the host's thymus epithelium and not against DB because it is not expressed by the reconstituting lymphoreticular system. (KBIB/DA) leads to (KCIC/DA) K, I incompatible, or completely H-2 incompatible A leads to B chimeras fail to generate any measurable virus specific cytotoxicity, indicating the necessity for I-specific helper T cells for the generation of killer T cells. Finally adult thymectomized, irradiated and bone marrow reconstituted (A X B)F1 mice, transplanted with an irradiated thymus of A origin, generate virus-specific cytotoxic T cells specific for infected A targets but not for B targets; this result formally demonstrates the crucial role of thymic epithelial cells in the differentiation of anti-self-H-2 specificities of T cells.
833 citations
"In irradiation chimeras, K or D reg..." refers background or methods in this paper
...Thus, stem cells expressing D k cannot respond to D k plus vaccinia whether selected in a thymus of H-2D k or H-2 b type as was shown previously (8, 9)....
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...The methods for making irradiation bone marrow chimeras have been described (8, 9, 10, 12)....
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TL;DR: A central function of the major histo-compatibility (H) antigens may be to signal changes in self to the immune system, with extreme genetic polymorphism found in the major H antigen systems of higher vertebrates reflecting evolutionary pressure exerted by this immunological surveillance mechanism.
464 citations
"In irradiation chimeras, K or D reg..." refers background in this paper
...However, it cannot be excluded t ha t / r effects may be expressed at the level of antigen presentation, determined by the capacity of viral antigen to "complex" more or less immunogenically with the restricting K or D structures (3, 4)....
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TL;DR: Dinitrophenyl poly-L-lysine complete Freund's adjuvant delayed-type hypersensitivity immune response immune suppression bovine serum albumin ovalbumin poly (L-glu^- L-lys"") poly ( L- gluTM-L -tyr5») guinea pig albumin major histocompatibility complex
Abstract: dinitrophenyl poly-L-lysine complete Freund's adjuvant delayed-type hypersensitivity immune response immune suppression bovine serum albumin ovalbumin poly (L-glu^-L-lys\"\") poly (L-glu'^-L-ala*\") poly (L-gluTM-L-tyr5») guinea pig albumin major histocompatibility complex guinea pig major histocompatibility complex major histocompatibility complex-linked poly (I^glu^-L-ala^o-L-tyr'o) methylated bovine serum albumin thymus-derived (T) lymphocytes B lymphocytes plaque-forming cells peritoneal exudate T enriched lymphocytes trinitrophenyl cytolytic T lymphocjfte(s) poly (L-glu5«-L-lys^-L-phe') poly (L-glu«-L-lys\"-L-alai») T-lymphocyte derived suppressor factor C57BL/6 C57BL/10 poly (I^tyr, L-glu)-poly-DI^ala-poly-L-lys poly (L-tyr, L-glu)-poly-L-pro-poIy-I^lys poly (L-phe, L-glu)-poly-DL-ala-poly-L-lys poly (L-his, I^glu)-poly-DL-ala-poly-L-lys
370 citations
"In irradiation chimeras, K or D reg..." refers result in this paper
...These results and models are compatible with Ir effects regulating T-helper cells (4, 5), and T cells specific for the male H-Y antigen (6, 7)....
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TL;DR: The results are consistent with the hypothesis that diversity of T-cell receptors is generated by somatic mutation of germ-line genes encoding specificity for self-H-2.
Abstract: Female murine T cells can respond to the Y antigen of male cells by generating cytotoxic T-killer lymphocytes. Responsiveness is linked to several H-2 genes. Two types of low responders can be distinguished: the B10.A(5R) (H-2i5) strain, a low responder because it lacks Y-specific precursor T cells able to differentiate into cytotoxic T-killer cells; and the CBA/J (H-2k) strain, a low responder because it lacks Y-specific T-helper cells able to support differentiation of T-killer cell precursors. B10.A(5R) stem cells differentiating in an x-irradiated (CBA/J X C57BL/6) (H-2k X H-2b)F1 host respond to Y antigen by generating T-killer cells whereas CBA/J stem cells do not. The results are consistent with the hypothesis that diversity of T-cell receptors is generated by somatic mutation of germ-line genes encoding specificity for self-H-2. A detailed account of this hypothesis is presented.
332 citations
"In irradiation chimeras, K or D reg..." refers background or methods in this paper
...Whether this Ir effect is quantitative or qualitative probably reflects the size or the number of the antigenic determinants and the number of antigen-specific T-cell precursors (1, 2, 12)....
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...The methods for making irradiation bone marrow chimeras have been described (8, 9, 10, 12)....
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TL;DR: If T cells learn in the thymus to recognize H-21 or K, D markers that are not at least partially carried themselves in other cells of the lymphoreticular system immunological interactions will be impossible and this paradox situation results in phenotypic immune incompetence in vivo.
Abstract: The thymus determines the spectrum of the receptor specificities of differentiating T cells for self-H-2; however, the phenotypic expression of T cell's specificity for self plus virus is determined predominantly by the H-2 type of the antigen presenting cells of the peripheral lymphoreticular system Furthermore, virus specific helper T cells are essential for the generation of virus-specific cytotoxic T cells For cooperation between mature T cells and other lymphocytes to be functional in chimeras, thymic epithelial cells and lymphohemopoietic stem cells must share the I region; killer T-cell generation also requires in addition compatibility for at least one K or D region These conclusions derive from the following experiments: A leads to (A X B)F1 chimeric lymphocytes do produce virus-specific cytotoxic T-cell activity for infected A but not for infected B cells; when sensitized in an acutely irradiated and infected recipient (A X B)F1 these chimeric lymphocytes respond to both infected A and B Therefore the predominantly immunogenically infected cells of chimeras the radiosensitive and by donor stem cells replaced lymphoreticular cells In this adoptive priming model (KAIA/DB leads to KAIA/DC) chimeric lymphocytes could be sensitized in irradiated and infected F1 against KA and DC but not against infected DB targets In contrast KBIB/DA leads to KCIC/DA chimeras' lymphocytes could not be sensitized at all in appropriately irradiated and infected F1 recipients Thus these latter chimeras probably lack functional I-specific T helper cells that are essential for the generation of T killer cells against infected D compatible targets If T cells learn in the thymus to recognize H-21 or K, D markers that are not at least partially carried themselves in other cells of the lymphoreticular system immunological interactions will be impossible and this paradox situation results in phenotypic immune incompetence in vivo
267 citations
"In irradiation chimeras, K or D reg..." refers background or methods in this paper
...For example, (C3H × C57BL/6) ~ C57BL/6 chimeras (group 1) generate T cells that express restriction specificity for K b and D b, but not for Kk; since the immunogenic lymphoreticular system of the chimera is of donor (H-2 k × H-2 n) type (9), immunogenic K k plus vaccinia is expressed on macrophages, but cannot be recognized by the T cells of this chimera....
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...Similarly, C3H ~ C3H × C57BL/6 chimeric spleen cells that were adoptively sensitized in acutely irradiated and infected (C3H X C57BL/ 6)F1 sensitizing recipients (group 10) lysed H-2 k and H-2 b targets, but not infected D b targets (9)....
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...Thus, stem cells expressing D k cannot respond to D k plus vaccinia whether selected in a thymus of H-2D k or H-2 b type as was shown previously (8, 9)....
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...The methods for making irradiation bone marrow chimeras have been described (8, 9, 10, 12)....
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