Involvement of Lyt-2 and L3T4 in activation of hapten-specific Lyt-2+ L3T4+ T-cell clones.

Abstract

The murine T-cell surface molecules Lyt-2 and L3T4 play a role in the activation of antigen-specific T cells. The currently accepted model for the function of these molecules proposes that Lyt-2 and L3T4 increase the overall avidity of the interaction between the T-cell antigen receptor and antigen in association with the major histocompatibility complex (MHC) molecules on the antigen-presenting cell. We have used two unusual Lyt-2+ L3T4' class II MHC-restricted T-cell clones to test whether Lyt-2 can substitute for L3T4 when the T-cell antigen receptor is class 11 MHC-restricted. Monoclonal antibodies against L3T4 profoundly inhibited antigen-induced lymphokine production by both T-cell clones. Anti-Lyt-2 monoclonal antibody had no effect. These results strongly suggest that L3T4 and the class 11-restricted T-cell antigen receptors are physically close during antigen recognition, probably as part ofa multimolecular complex from which Lyt-2 is excluded. The ability of L3T4 but not Lyt-2 to participate in such a complex with class 11-restricted T-cell antigen receptors may explain the striking correlation between class II restriction and L3T4 expression in the peripheral T-cell pool.Activation of T lymphocytes depends not only on clonally distributed T-cell antigen receptors (TcR) but also on a number of relatively invariant surface glycoproteins such as Lyt-2 and L3T4 (homologous to the human T8 and T4 antigens, respectively). In general, these two molecules are expressed in a mutually exclusive fashion on mature T cells and have therefore been used to define T-cell subsets.The vast majority of Lyt-2' cells recognize antigen in association with a product of the class I major histocompatibility complex (MHC) genes, whereas expression of L3T4 is characteristic ofthe class II-restricted subset ofT cells (1). At the population level, most of the cytotoxic/suppressor function resides within the Lyt-2' subset, whereas helper capability is a function of the L3T4' subset. However, the correlation between T-cell function and the expression of Lyt-2 or L3T4 is weaker than that between MHC-restriction pattern and Lyt-2/L3T4 expression.Evidence implicating Lyt-2 and L3T4 in T-cell activation comes from antibody-mediated blocking experiments. Antibodies to Lyt-2 can simultaneously inhibit cytotoxicity, proliferation, and lymphokine production by Lyt-2' T-cell clones (reviewed in refs. 2 and 3), suggesting that Lyt-2 is involved in the initial antigen-recognition event. However, there is marked variation in the degree to which anti-Lyt-2 antibodies inhibit activation of individual T-cell clones. Such variation is not a function of the amount of Lyt-2 on the T-cell surface but appears to correlate negatively with the affinity of the TcR for antigen in association with MHC molecules (antigen-MHC). Thus, secondary anti-allo-MHC responses are far more difficult to inhibit than are primary responses (2).Further support for this interpretation has been provided by the observation that anti-viral clones (from a secondary res...

Coaggregation of the T-cell receptor with CD4 and other T-cell surface molecules enhances T-cell activation.

“…The inhibition of T-cell activation by anti-CD4 antibodies in the absence of interactions with class II MHC is consistent with the related proposition of an interaction between CD4 and the TCR complex, also contributing to T-cell activation, independently of interactions with MHC (10). Our previous analysis of the effects of anti-L3T4 antibodies on the activation of class II MHC-restricted T cells by anti-TCR antibody suggested that antibodies recognizing L3T4 inhibit activation through steric hindrance of the formation of TCR complexes (11).…”

Simultaneous expression of CD4 and CD8 antigens by a substantial proportion of resting porcine T lymphocytes

“…In murine CD4+CD8+ clones, the CD8 molecules were found to be expressed as Lyt-2 homodimers, which did not participate in antigen recognition that was class I1 restricted and involved only the CD4 molecule [20]. It is questionable, however, whether these rare murine clones are representative of doubleexpressing T lymphocytes in general.…”

CD4 and CD8 molecules can physically associate with the same T-cell receptor.

“…Third, antibody-induced crosslinking ofthe TCR with its accessory CD4 or CD8 abrogated the inhibitory effect of anti-CD4/CD8 mAbs and could even enhance T-cell activation (6,9,10). These observations have underpinned the hypothesis that, at the time of antigen recognition, CD4 and not CD8 must form a close physical association with its class II-restricted TCR on the T-cell surface; conversely, CD8 would associate exclusively with a class I-restricted TCR (5,9).…”