H-2K/H-2D and Mls and I region-associated antigens stimulate helper factor(s) involved in the generation of cytotoxic T lymphocytes.
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This study examines the antigen that stimulate production or release of a soluble helper factor(s) involved in development of cytotoxic T lymphocytes (CTL). Antigens associated with the Mls locus, I and K/D regions of the MHC were all capable of stimulating responder cells in MLC to produce helper factor. These supernatant fluids were all capable of providing "help" for the generation of cytotoxic T lymphocytes in MLC in which spleen cells are stimulated by allogeneic heat-treated thymocytes or splenocytes. Previous reports from our laboratory as well as others have shown that heat-treated cells do not stimulate a cytotoxic response. Heat-treatment of Mls, I, and H-2K/H-2D region incompatible stimulatory cells in MLC eliminated their ability to induce responder cells to produce helper factor, suggesting this is the mechanism whereby heat-treatment reduces the ability of cells to stimulate cell-mediated lympholysis (CML). The inability of supernatant fluids, from MLCs in which heat-treated cells were the stimulators, to assist in the generation of cytotoxic T cells did not appear to be the result of any suppressive factor induced by such treatment. Further, the antigens that stimulate pre-killer cells appear functionally distinct from those heat labile antigens (Mls, I, H-2K/H-2D associated) that stimulate helper factor production since heat-treated allogeneic cells served as stimulators of cytotoxicity provided helper activity was added to the MLC.Keywords:
Splenocyte
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Analysis of creatol (CTL, 5-hydroxycreatinine), an oxidative creatinine (Cr) metabolite, in serum and urine of human subjects has indicated that CTL is a useful determinant of renal function. The existence itself of serum CTL (s-CTL) could be a diagnostic sign for chronic renal failure (CRF): in all normal subjects, s-CTL was undetectable, but s-CTL was detectable in sera of all patients with CRF (s-Cr: > 2.0 mg/dl). And the s-CTL values increased in proportion to the severity of CRF in such patients. Furthermore, the molar ratio (CTL/Cr) in both urine and serum increased significantly in proportion to the severity of CRF. Our results indicated not only hyperproduction of CTL but also higher oxygen stress in patients according to the progression of CRF. The diagnostic importance of the CTL value and the CTL/Cr ratio are discussed.
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The immunosuppressive drug Cyclosporin A (cyclosporine) inhibits the reactivation of quiescent Ag-dependent CTL in the presence of IL-2. Both proliferation and the regeneration of cytotoxicity are inhibited. The cytotoxic cells that are inhibited are Ag dependent for activation, whereas derived, Ag-independent, but still IL-2-dependent, cytotoxic cells are insensitive to cyclosporine. Cyclosporine also directly inhibits the effector phase of the cytotoxic cells, although not completely. The generation of primary CTL in mixed cultures was also blocked by cyclosporine in the presence of IL-2, in a time-dependent way that indicated that the sensitive time was early during the cultures. The CTL generated in primary cultures were significantly inhibited by cyclosporine in the assay, but this inhibition was less than for the cloned CTL lines.
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It has been assumed that the maturation of pre-CTL to virus-specific effector CTL is dependent upon IL-2-mediated T cell triggering through the IL-2R. In view of its similarity to IL-2 in its effects on immune cells, we sought to determine whether IL-15 can induce the expansion of AIDS virus-specific pre-CTL to mature CTL. PBL of SIV(mac)-infected rhesus monkeys or HIV-1-infected humans have previously been shown to expand to effector CTL when cultivated with a predicted CTL epitope peptide and rIL-2. We now demonstrate that rIL-15 facilitates this expansion of effector CTL. In fact, rIL-15-driven expansion of virus-specific CTL occurs in the presence of IL-2-neutralizing or anti-IL-2R Abs, indicating that this cellular maturation can occur in an IL-2-independent fashion. These studies suggest a mechanism by which CTL may be capable of expanding in vivo in the absence of IL-2 and functional CD4+ T lymphocytes.
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Abstract A limiting dilution assay was used to compare the frequency of cytotoxic T lymphocyte precursors (CTL‐P) which respond to H‐2 antigens presented with additional background differences, with the frequency of CTL‐P which respond to H‐2 antigens on a self background. Individual cultures were divided and assayed for cytotoxic activity on the two targets sharing H‐2, but not the background; no cultures were seen which clearly killed one and not the other, and the same frequency of CTL‐P was measured on target cells that differed from the responder only at H‐2 and on target cells that differed also in the background, irrespective of the background of the stimulator. Thus, the assumption that allospecific cytotoxic T lymphocytes (CTL) recognize H‐2 plus minor histocompatibility antigens does not serve as an adequate explanation for the high frequency of allospecific CTL. The data also suggest that the two allelic forms of β 2 ‐microglobulin do not contribute to the alloantigenic determinant.
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Histocompatibility
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MHC restriction
Pan-T antigens
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The cytotoxic T-lymphocyte (CTL) response to lymphocytic choriomeningitis virus infection determines the outcome of infection. Here we show that this response in BALB/c mice (H-2d), when analyzed both at the primary CTL level and using CTL clones, is predominantly monospecific. The vast majority of CTL have a common specificity for a single epitope in the virus nucleoprotein, which can be minimally identified by amino acids GVYMG. This epitope is presented by the Ld class I glycoprotein. We used these data to design a subunit CTL vaccine, whose effectiveness is demonstrated in the accompanying report (L. S. Klavinskis, J. L. Whitton, and M. B. A. Oldstone, J. Virol. 63:4311-4316, 1989). Further analysis indicates that, while CTL clones share a common minimal epitope, they differ in their ability to recognize cells infected with a related but distinct strain of lymphocytic choriomeningitis virus. Studies on the molecular nature of CTL cross-reactivity indicate that CTL induced by similar sequences may cross-react in a unidirectional manner. These novel observations suggest that CTL vaccines, to achieve optimal effectiveness, should not simply include virus sequences which will yield a CTL response; the immunizing sequences should also be selected to ensure that the fine specificities of the induced CTL are such that they maximize the chance of recognizing serotypically diverse strains.
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A limiting‐dilution system was established to measure the frequency of alloreactive cytotoxic T‐lymphocyte precursors (CTL‐p) in human peripheral blood T cells. Culture medium supple mented with recombinant interleukin‐2 enabled clonal expansion of all CTL‐p stimulated by allogeneic peripheral blood or spleen cells. The range of CTL‐p frequencies in fully HLA‐mismatched responder‐stimulator combinations was 1:240 to 1:1230. Split‐well analysis of individual microwells showed that the cytotoxic T‐cell clones generated under limiting‐dilution conditions showed exquisite specificity for the stimulating alloantigens. Alloreactive CTL‐p were enriched in the OKT4 T‐cell subset. This limiting‐dilution system was highly reproduci ble and can thus be applied to investigate human cytotoxic T‐eell precursor frequencies in various clinically relevant situations.
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Computation tree logic
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Abstract We reported previously that the mouse tumor P815 expresses four distinct antigens (A, B, C, D) recognized by syngeneic cytolytic T lymphocytes (CTL). A fifth P815 antigen (E) was identified by means of a CTL clone derived from tumor‐infiltrating lymphocytes. We compared a number of mice for the orientation of their CTL response with respect to the various P815 antigens. Lymphocytes from mice inoculated subcutaneously with living P815 cells were stimulated in vitro with tumor cells and the resulting CTL were tested against targets expressing either antigens A and B or antigens C, D and E. Many mice had an asymmetrical response, some producing CTL directed almost exclusively against antigens A, B and others producing CTL directed almost exclusively against C, D. E. When mice were inoculated into two separate sites, different orientations in the responses of the two local lymph nodes were often observed, suggesting that individual differences in the orientation of the anti‐P815 CTL response do not result from preexisting differences between the animals. Asymmetrical CTL responses persisted in mice that were given a second injection of tumor cells. A possible interpretation of our results is that the major component of the CTL response is made of the progeny of a very small number of CTL precursors that happen to be the first to be stimulated by the tumor antigens.
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clone (Java method)
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