No abstract

Summary The number and function of human T cells in the periphery are regulated by homeostatic signals received from antigen‐presenting cells (APCs) and the common gamma chain (γc) cytokines interleukin (IL)‐7 and IL‐15. We found that, in the absence of introduced antigen, blood monocytes or myeloid dendritic cells (MDCs) in the presence of IL‐7 and IL‐15 (IL‐7/IL‐15) can regulate CD4+ T memory (Tm) cell numbers by polyclonal cell proliferation. The dynamics of CD4+ Tm cell proliferation, in the presence of IL‐7/IL‐15, was dependent on contact with MDCs and to a lesser extent on contact with monocytes. IL‐7/IL‐15 either alone or combined with monocytes or MDCs enhanced the proportion of CD4+ Tm cells with activated and effector phenotype and diminished the helper function of CD4+ Tm cells. These CD4+ Tm cells, preconditioned with IL‐7/IL‐15 alone or with monocytes or MDCs and IL‐7/IL‐15, reduced T cell‐dependent immunoglobulin M (IgM) and IgG responses. This appeared to be a contact‐dependent effect involving a reduction in antibody‐producing CD27+ B memory cells, but contact‐independent suppression by soluble factors also contributed to the antibody‐producing capacity of CD27+ B memory cells. These results indicate that blood monocytes, MDCs and the cytokines IL‐7/IL‐15 contribute to homeostasis of CD4+ Tm cells by regulating their number, activation state and helper/suppressor (regulatory) function. In healthy individuals, this mode of regulating CD4+ Tm cell homeostasis may provide a basis for the control of autoimmune responses.

We are investigating the possibility that farnesyl transferase inhibitors (FTIs) may be useful anti‐rejection drugs. We have shown that the FTI, L‐744,832 can significantly delay allograft rejection in mice using MHC class II mismatched skin allografts. When treatment with this FTI begins two days prior to the allograft procedure and extends for 5 days, we found that rejection was delayed in all treated mice, 26±14 days, compared to untreated mice, 13±4 days. Interestingly, this delay in rejection can extend for greater than 30 days in 30% of the treated mice. To determine whether FTI treatment can delay alloreactive effector responses, we examined the effect of L‐744,832 treatment on allograft rejection in mice that had previously been sensitized to the allo‐antigens. We found that treatment with this FTI did not significantly delay second‐set allograft rejection. This observation, coupled with the long delay in some of the first set allograft treatments, suggests that FTIs may be able to induce tolerance of the alloreactive CD4+ T cells. To further investigate the action of FTIs on graft rejection we are measuring the effects of treatment using mixed lymphocyte cultures and using in vivo tolerance assays. We suggest that FTIs may modulate acute immune responses without systemically suppressing the immune system.