The dual specificity of thymus-derived lymphocytes (T cells) for structures coded by the major histocompatibility gene complex (MHC) 1 and for foreign antigens (X) appears to be a general finding in mice and is likely to be a more universal phenomenon in higher vertebrates. Thus, all T-cell functions that have been tested in mice i.e., T cells involved in nonlytic helper, delayed type hypersensitivity, and macrophage activation functions are specific for the murine MHC (H-2) coded structure mapping to the I region (1-5), whereas cytotoxic T-cell activity is specific for H-2K or D (6-11). Similarly, cytotoxicity appears to be MHC-restricted in the rat (12), in humans (13), and in chickens (14). This restriction of T cells by MHC determinants contrasts with the apparently complete absence of H-2 restrictedness of B-cell functions or of their antibody products.Although the phenomenology is clear and well accepted, the explanation of it is controversial and therefore many hypotheses and speculations have attempted to catch the elusive nature of the T-cell receptor; because it is generally felt that this dual specificity of T cells reflects and may therefore reveal unique properties of the T-cell receptor(s). Two models of associative T-cell recognition have been proposed: first the dual recognition model (1-9, 14, 15) where T cells recognize two distinct antigenic entities i.e., self-H-2 structures and foreign antigen X with two separate receptors. Second, the single receptor model, which proposes that T cells possess one single receptor specificity that recognizes a neoantigenic determinant (NAD) formed either by a complex of self and

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.

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Congenitally thymusless nude mice that lacked functional T cells were reconstituted with H-2-compatible or -incompatible thymus grafts taken from either fetal, newborn, or adult mice and transplanted under the kidney capsule or subcutaneously. Transplantation with unirradiated fetal (15--17 d) or newborn thymus grafts reconstituted the nude mice as assessed by their subsequent generation of virus-specific cytotoxic T cells in vivo or alloreactive T cells in vitro. The restriction specificity of T cells from homozygous mice was exclusively for the nude host H-2, as shown by direct cytolysis or by cold target competitive inhibition assays. irrespective of whether nude mice were reconstituted with H-2-compatible, semiallogeneic, or H-2-incompatible, unirradiated newborn or fetal thymus grafts (in order of decreasing efficiency of reconstitution). The restriction specificity for the nonhost H-2 of the thymus could not be demonstrated even after primary or secondary sensitization in an infected appropriate F1 environment. These nude mice reconstituted with fetal or newborn grafts were tolerant to the H-2 of the thymus donors. Nude mice transplanted with irradiated adult thymus grafts were reconstituted functionally with syngeneic or semisyngeneic but not with allogeneic thymus grafts. In homozygous nu/nu irradiated heterozygous recipients of F1 thymus grafts, the restriction specificity for the nonhost thymic H-2 could not be elicited upon adoptive sensitization in irradiated and infected F1 heterozygote stimulator mice; in fact, these chimeras' lymphocytes were not tolerant to the nonhost H-2. The discrepancy between the restorative capacity of unirradiated vs. irradiated thymus grafts suggests that precursors of T cells in nude mice can acquire restriction specificity and immunocompetence independently of a conventional, functioning H-2-compatible thymus if exposed to an allogeneic fetal or a newborn thymus that contains functioning thymocytes of donor type but not if reconstituted with an irradiated adult allogeneic thymus.