On the mechanism of human T cell suppression.

Previous evidence from several laboratories suggests that CD8+ T suppressor cells may be important regulatory elements governing specific unresponsiveness of lepromatous lepromatous leprosy patients to M.leprae. To analyse the mechanism of suppression, CD8+ Ts clones were established from lesions and peripheral blood of lepromatous patients and tested for ability to suppress antigen-responsive CD4+. Th clones or PBL. Suppression required induction by specific M.leprae antigen, but was effected in an antigen-non-specific fashion. The Ts clones failed to exhibit cytotoxicity of four antigen-exposed MHC-matched target cells: (i) an ori-SV40 transformed macrophage line; (ii) EBV transformed B cell lines; (iii) primary macrophages; and (iv) M.leprae responsive CD4+ cells. The possibility that Ts clones induce functional inactivation of CD4+ clones in vitro was investigated. M.leprae-responsive CD4+ clones were preincubated with Ts CD8+ clones, APC, and antigen for 16 h, after which the CD8+ cells were removed. The CD4+ clones with M.leprae and APC remained unresponsive to restimulation with APC and antigen for at least 10 days, although they responded to IL-2. Addition of IL-2 to the pre- or post-incubation cultures neither prevented the induction of unresponsiveness, nor reversed it. Earlier models of tolerance have suggested that receptor occupancy in the absence of second signals induces tolerance in B and T cells. Under conditions in which antigen responses of Th clones were HLA-DR-restricted, the Ts clones were able to suppress the response of DR mismatched Th clones. Thus, the effect of the Ts cells, like mechanisms requiring antigen presentation without a second signal, appears to be induction of clonal anergy in Th cells, perhaps by a novel mechanism.