Differential susceptibility of human T(h)1 versus T(h)2 cells to inductionof anergy and apoptosis by ECDI/antigen-coupled antigen-presenting cells

Antigen-coupled antigen-presenting cells (APC) serve as potent tolerogens f or inhibiting immune responses in vivo and in vitro, apparently by providin g an antigen-specific signal through the TCR in the absence of co-stimulati on, Although this approach has been well studied in rodents, little is know n about its effects on human T cells. We evaluated the specificity and mech anisms of tolerization of human T cells in vitro using monocyte-enriched ad herent cells that were pulsed with antigen and treated with the cross-linke r, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI), Autologous antige n-coupled APC selectively tolerized T cells of the T(h)1 but not T(h)2 line age through a mechanism that involved both antigen-specific and antigen-non -specific elements. The tolerization process was dependent on the ECDI and antigen concentration, and the coupling time, and was reflected by initial up-regulation of CD25, However, upon re-stimulation with fresh APC and anti gen, tolerized T(h)1 cells failed to proliferate or to produce T(h)1 cytoki ne message or secreted protein, had decreased expression of CD25, CD28 and B7 and increased expression of MHC class II molecules, and demonstrated an enhanced commitment to apoptosis, T(h)1 cell tolerization could be prevente d by adding anti-CD28 antibody, IL-2 or untreated APC at the same time as t he ECDI/ antigen-coupled APC, or reversed by adding anti-CDS8 antibody or I L-2 upon re-stimulation with fresh APC plus antigen. Thus, the tolerizing e ffect of ECDI/antigen-coupled APC on human T(h)1 cells appears to involve a reversible anergy mechanism leading to apoptosis, whereby the targeted T c ells receive full or partial activation through the TCR, without coordinate co-stimulation, These data suggest dichotomous signaling requirements for inactivating cells of the T(h)1 and Th2 lineages that may have important im plications for treatment of T(h)1-mediated autoimmune or inflammatory disea ses.