STUDIES OF THE AUTOLOGOUS MIXED LYMPHOCYTE REACTION

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This project is directed toward the study of the autologous mixed lymphocyte reaction (AMLR), the proliferative response of T cells brought about by their exposure to autologous B cells and macrophages. In the present series of studies we report on the establishment of autoreactive T cell clones and the nature of the immunoregulatory capacity of such clones. In initial studies we found that autoreactive T cells develop in cultures repetitively stimulated by antigen (tetanus toxoid) presented by autologous non-T cells (in the presence of IL-2). Such cells appear along with antigen-reactive T cells, but can be isolated from the latter and then expanded using limiting dilution techniques. One of the autoreactive clones, termed MTC-4, has the phenotype of "helper" cell (Leu3+, Leu2-) and undergoes proliferation when co-cultured with autologous, but not allogeneic non-T cells. Of interest, the immunoregulatory potential of MTC-4 cells varied according to how the cells were activated. When MTC-4 cells were cultured with autologous non-T cells in the absence of antigen or mitogen, polyclonal immunoglobulin production was observed. This helper activity was MHC-restricted in that it was elicited only by autologous non-T cells or MHC matched allogenic non-T cells; however, once activated by autologous non-T cells, MTC-4 cells could also help allogeneic non-T cells. In contrast, when MTC-4 cells were cultured with autologous non-T cells in the presence of pokeweed mitogen (PWM), immunoglobulin production was suppressed. This suppression was not due to a direct effect of PWM on MTC-4 cells, since pre-incubation of the latter with PWM prior to culture with non-T cells did not result in suppression. On the basis of these data, we conclude that autoreactive T cells have dual regulatory capability which is differentially elicited by the mode of activation: 1) when stimulated by MHC antigens present on unactivated B cells, they provide helper activity; and 2) when stimulated by MHC antigens present on activated B cells, they provide suppressor activity. Autoreactive cells with these properties are uniquely adapted to maintain immunologic homeostasis.