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: 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.
1,858 citations
TL;DR: This chapter opens up with a detailed analysis of the early experiments of these scientists, culminating in the discovery by McDevitt that these genes were linked to the major histocompatibility complex (MHC).
Abstract: Publisher Summary This chapter opens up with a detailed analysis of the early experiments of these scientists, culminating in the discovery by McDevitt that these genes were linked to the major histocompatibility complex (MHC). One of the major unifying threads in cellular immunology that ended in the identification of MHC-encoded molecules as the Ir gene products and the merging of the two phenomena: Ir gene control and MHC restriction (the requirement for T cells to recognize an MHC-encoded molecule in addition to the antigen in order to become activated). The recent developments in cellular and molecular cloning have moved the problem of Ir gene function to the biochemical level. Ir genes are genetically linked to the MHC. A formal proof of the genetic linkage of Ir-genes to the MHC was performed using the segregating population in a backcross to the low responder parent.
207 citations
TL;DR: Examining the turnover of APCs in the thymuses of F1→parent (P) radiation-induced bone marrow chimaeras found that APCs of donor phenotype appear at about 2 months after reconstitution, suggesting that cells from the bone marrow can influence thymic-directed T-cell differentiation.
Abstract: Experiments with chimaeric animals have demonstrated that the H-2 restriction specificity and immune response (Ir) gene phenotype of the T cell is acquired during development in the thymus. The mechanism by which this process occurs is unclear. One level of obligate expression of H-2 and Ir gene products is on the surface of antigen-presenting cells (APCs) which come from bone marrow precursors. We have now examined the turnover of APCs in the thymuses of F1 leads to parent (P) radiation-induced bone marrow chimaeras and found that APCs of donor phenotype appear at about 2 months after reconstitution. If the peripheral T-cell population is depleted after this time, new T cells emerging from the parental thymus (containing F1 APCs) behaving like F1 T cells, suggesting that cells from the bone marrow can influence thymic-directed T-cell differentiation. The thymic APC is an attractive condidate to play such a part in the development of the T-cell repertoire.
149 citations
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.
55 citations
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...(11), who used H-2/r-regulated trinitrophenol cross-reactivity (11), and by von Boehmer et al....
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