No abstract

Human T cells respond strongly to mouse major histocompatibility complex (MHC) antigens. The response is directed predominantly to the polymorphic determinants of the MHC antigens and there is little or no response to the nonpolymorphic determinants or to non-MHC antigens. Human cytotoxic T lymphocytes (CTL) are generated specific for the mouse class I MHC antigens and the CTL effectors are blocked by anti-Leu-2a antisera. Human interleukin 2-producing T cells are generated specific for mouse class II antigens and their induction is blocked by anti-Leu-3a antisera. These and other considerations lead us to propose a model for the T cell receptor that provides an explanation for several of the features of T cell recognition. In this model, the recognition of the "class" (I or II) of MHC antigen is separate from the recognition of the polymorphic determinants. We suggest that the initial recognition of the conserved "class" determinants positions another domain of the receptor so that it can only engage with the part of the MHC molecule carrying the polymorphic determinants.

Aged humans and experimental animals are impaired in their responses to most foreign antigens although they produce greater amounts of autoantibodies. We have examined the effect of age on the production of antibodies to a prototypic foreign antigen, sheep erythrocytes (SRBC), and to a prototypic autoantigen, bromelain-treated mouse erythrocytes (BrMRBC), in young and old mice before and after immunization with SRBC. Old mice express more anti-BrMRBC plaque-forming cell (PFC) antibodies before and an even greater number after immunization with SRBC than young mice. Conversely, old mice produce far fewer anti-SRBC PFC than young mice following immunization with SRBC. We hypothesized that the differences in the responses of old mice to BrMRBC and SRBC reflects differences in the activity of CD5+ and CD5- B cells. To test this hypothesis we immunized young and old mice with foreign antigens reported (and confirmed in our studies) to stimulate CD5+ B cells [TNP-ficoll and phosphorylcholine-keyhole limpet hemocyanin (KLH)] or CD5- B cells (SRBC and TNP-KLH). We found that the PFC response of old mice to antigens mediated by CD5+ B cells was equal to or greater than that of young mice. In contrast the PFC response of old mice induced by antigens mediated by CD5- B cells was only 10% that of young mice. Thus it appears that the immune response of old mice is well maintained for antigens which elicit a CD5+ B cell response but not for those which elicit a CD5- B cell response.(ABSTRACT TRUNCATED AT 250 WORDS)

Immune recognition by cytotoxic effector T cells requires participation of the CD8 and major histocompatibility complex class I antigens. We found that the CD8 molecule is noncovalently associated with the HLA class I heavy chain on the surface of human T cells activated by Con A. Accordingly, anti-CD8 monoclonal antibodies precipitated a heterodimer containing polypeptides of32 and 43 kDa from the lysates of activated T cells. tigen and polymorphic MHC determinants (5-8). This recognition appears to be a complex process, and at least one additional cell surface component, the CD8 molecule, is implicated (4, 9-11). CD8 has been characterized as a 32-to 34-kDa integral membrane protein in its reduced form (12,13). Under nonreducing conditions, CD8 has been identified in a series of multimeric forms differing in inter-or intrachain disulfide bonding (13). Studies have suggested (1-4, 14-16) that CD8 can bind to MHC class I molecules and thereby increase T-cell-target or T-cell-accessory-cell avidity that allows recognition of antigen and T-cell activation. To date, however, the actual physical interaction between CD8 and MHC class I molecules on T-cell surface is not well understood. This report demonstrates a noncovalent association between CD8 and HLA heavy chain molecules on the surface of activated human T cells.MATERIALS AND METHODS Cells. Human thymocytes and peripheral blood T cells isolated by forming rosettes with sheep erythrocytes (17) were used directly for radioiodination. For Con A activation, T cells were incubated at 106 cells per ml with 10' non-T cells per ml in complete medium [RPMI 1640 medium with 5% (vol/vol) fetal bovine serum, glutamine (0.06 mg/ml), streptomycin (100 tg/ml), and penicillin (100 units/ml)] with Con A (10 pkg/ml) for 2 days. Before radioiodination, the Con A-activated T cells were washed once with 50 mM a-methyl mannoside (Sigma) and twice with isotonic phosphatebuffered saline (pH 7.2). For allogeneic activation of T cells, unseparated peripheral blood lymphocytes from two healthy donors were incubated in complete medium at 2 x 106 cells per ml for 5 days. A natural killer (NK)-enriched cell population obtained by discontinuous Percoll gradient centrifugation (18) was 80% positive for CD16, recognized by monoclonal antibody B73.1 (19). A cloned CTL line (CD3 +, CD4 -, CD8 '), derived from peripheral blood lymphocytes sensitized with irradiated allogeneic non-T cells, was maintained in RPMI 1640 medium with 20% (vol/vol) pooled human AB serum (Flow Laboratories) and human interleukin 2 (20 units/ml) (Boehringer Mannheim). The human T-cell leukemia line HPB-ALL was from J. Minowada (Roswell Park Memorial Institute, Buffalo, NY) and was maintained in complete medium.Antibodies. The monoclonal antibodies OKT8A (Ortho Diagnostics), anti-Leu-2a (Becton Dickinson), and C8 (20) (a gift of C. Y. Wang, United Biomedical, Lake Success, NY) recognize CD8. The anti-HLA-A, -B, and -C monoclonal antibodies W6/32 (21) and A1.4 (22) The publication costs of this article were defr...

Positive selection of T cells within the thymus gland leads to major histocompatibility complex (MHC)-restricted recognition of antigen by T lymphocytes. As the thymus gland involutes with age, altered MHC-restricted antigen recognition by T cells from elderly humans would be expected. We have tested this hypothesis by comparing the proliferative response of T cells and T cell clones from aged and young subjects to influenza determinants presented by autologous or allogeneic antigen-presenting cells (APC). Under conditions in which the allogeneic mixed lymphocyte reaction was minimal, T cells from six of seven aged donors but only one of seven young donors were stimulated by influenza vaccine presented by allogeneic APC. More importantly, one-half of the influenza-specific T cell clones derived from aged donors, but none of the clones derived from young donors, were activated by influenza vaccine presented by allogeneic APC. While 80% of the MHC-nonrestricted influenza-specific T cell clones expressed the gamma/delta T cell receptor, 20% of these clones expressed the alpha/beta T cell receptor. Thus, changes in MHC-restricted antigen recognition by T cells and in altered distribution of alpha/beta versus the gamma/delta T cell receptor bearing antigen-specific T cell clones occur with aging.