In the present study we used an adoptive transfer model with athymic nude mice to characterize the T cells involved in initiating and mediating skin allograft rejection. It was found that skin allograft rejection in nude mice required the transfer of immunocompetent T cells and that such reconstitution did not itself stimulate the appearance of T cells derived from the nude host. Reconstitution with isolated populations of Lyt-2+/L3T4- T cells resulted in the rapid rejection of MHC class I-disparate skin allografts, whereas reconstitution with isolated populations of L3T4+/Lyt-2- T cells resulted in the rapid rejection of MHC class II-disparate and minor H-disparate skin allografts. By correlating these rejection responses with the functional capabilities of antigen-specific T cells contained within the reconstituting Lyt-2+ and L3T4+ T cell populations, it was noted that skin allografts were only rejected by mice that, as shown by in vitro assessment, contained both lymphokine-secreting Th cells and lymphokine-responsive Tk cells specific for the alloantigens of the graft. The ability of two such functionally distinct T cell subsets to interact in vivo to reject skin allografts was directly demonstrated in H-Y-specific rejection responses by taking advantage of the fact that H-Y-specific Th cells are L3T4+ while H-Y specific Tk cells are Lyt-2+. Finally, the importance of in vivo interactions between functionally distinct Th/T-inducer cells and T killer (Tk)/T-effector cells in skin allograft rejection was demonstrated by the observation that normal B6 mice retain Qala and Kbm6 skin allografts because of a selective deficiency in antigen-specific Th cells, even though they contain T-effector cells that, when activated, are able to reject such allografts. Thus, the ability to reject skin allografts is neither unique to a specialized subset of T cells with a given Lyt phenotype, nor unique to a specialized subset of helper-independent effector T cells with so-called dual function capability. Rather, skin allograft rejection can be mediated by in vivo collaborations between T-inducer cells and T-effector cells, and the two interacting T cell subsets can express different Lyt phenotypes as well as different antigen specificities.
A large number of studies have indicated that the activation of T helper cells for both antibody (1-6) and cytolytic T lymphocyte (CTL) 1 (7-11) 2 responses is restricted by products of the I region of the major histocompatibility complex (MHC), while the activation of CTL themselves is restricted by products of the K/D regions of the MHC (12-14). However, it is less clear how and when during their developmental pathway T ceils acquire their MHC-restricted self-recognition specificity. Studies with chimeras (12, 15, 16) and thymus-grafted nude mice (17, 18) have indicated that the MHC phenotype of the thymus dictates the particular MHC determinants that T cells recognize as self-recognition elements. In addition, the MHC phenotype of the extra-thymic environment has been implicated in the process that determines the restriction specificities of T cells (11,14,17,19,20). In vivo manipulation of the expression of MHC products may yield a better understanding of how the host environment (thymic or extra-thymic) determines restriction specificities of T ceils. One approach to achieving such manipulation is by in vivo administration of antibodies (Ab) to MHC products. A few reports describe the effect of in vivo anti-Ia Ab (5, 21-26) but no data on actual expression of I region products in the recipients are so far available. A recent report described suppression of B lymphocyte development in mice injected from birth with monoclonal anti-I-A Ab (27), i.e., surface Ia +, IgM ÷, and IgD ÷ B ceils did not develop in such mice.The purpose of the present study was to determine whether such chronic administration of anti-Ia Ab into mice during their first weeks of life might influence their T cell self-recognition repertoire. We show here that chronic injection of anti-I-A k Ab, starting in neonatal H-2 k mice, abrogates their ability to generate alloreactive and trinitrophenyl (TNP)-specific splenic CTL responses. Different mechanisms for this
An improved method is described for selecting mutant cells with an altered pattern of Ia antigenic determinants and antigen-presenting properties from an homogeneous population of functional antigen-presenting cells (APC). The APC line used, TA3, was a somatic cell hybrid obtained by fusing normal heterozygous H-2a/d B cells with a drug-marked variant of a BALB/c B lymphoma line. Two phenotypic groups of mutants were obtained by this method. Serologic analysis with a panel of anti-I-Ak monoclonal antibodies suggested that the change in the first group of mutants (type A mutants) involved the alteration of a portion of one epitope of the I-Ak molecule while in the second group of mutants (type B), an alteration of a different Ia epitope group had occurred. Functional studies using a panel of cloned antigen-specific and autoreactive T cell hybridomas demonstrated that the loss of a limited number of I-Ak determinants in the type A mutants correlated with the loss of some but not all I-Ak-encoded restriction elements, while the type B mutation(s) resulted in the ablation of all I-Ak-restricted APC functions tested. These mutations may occur in the region of the Ia molecule that interacts with the T cell receptor (the histope) or in a postulated region that interacts with antigen (the desetope). The finding that both type A and B mutations lead to loss in the capacity to be corecognized with many different antigens by I-Ak-restricted T cell hybridomas suggests that the Ia molecule may possess very few distinct histotopes and/or desetopes or that the tertiary structure of the Ia molecule is crucial in the formation of these sites. Alternatively, the mutations, particularly the type B mutations, may have led to the failure of expression of an entire alpha or beta chain.
Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.
Self-recognition and self-tolerance are two closely related yet distinct aspects of the T cell repertoire. Because the thymus is the organ within which T cells differentiate, it has been suggested that the thymus plays an important role in determining both aspects of the T cell repertoire. Indeed, there is evidence that the T cell repertoires for both self-recognition and allorecognition are influenced by the major histocompatibility complex (MHC) 1 determinants expressed by the thymus within which T cells mature (I-4). However, the mechanism by which the thymus exerts its influence on the developing T cell repertoire remains obscure. It is conceivable that the thymus either positively or negatively selects clones of T cells based on their expression of a predetermined receptor repertoire (5). Alternatively, it is conceivable that the thymus induces somatic mutations that result in the generation of new receptor specificities (6). One way of distinguishing between thymic selection of a predetermined T cell repertoire and the generation of a novel thymically induced T cell repertoire would be to first analyze T cell precursors for expression of MHC-specific receptors and then to compare the receptor repertoires expressed by precursor T cells before thymic processing with that expressed by T cells that have undergone thymic processing.Consequently, to eventually accomplish this sort of repertoire comparison, it is imperative to first know whether precursor T cells express MHC-specific receptors before thymic processing. It was recently observed that cytotoxic T lymphocytes (CTL) that were differentiating within a syngeneic thymus graft were tolerant to the allogeneic K/D determinants their precursors encountered on prethymic elements (7). Such results suggested that pre-T cells do express anti-MHC receptors specific for the recognition of K/D region-encoded determinants before their entry into the thymus. These results were consistent with observations that T cells from nude mice that have * Present address is Harvard Medical School,
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