A rheostatic mechanism for T-cell inhibition based on elevation of activation thresholds

The activation of discrete T-cell responses depends on the triggering of in dividualized threshold numbers of T-cell receptors (TCRs). The results of t his study indicate that the lipocalin placental protein 14 (PP14), a T-cell inhibitor produced by cells of the reproductive and hematopoietic systems, mediates its anti-inflammatory activity by elevating the T-cell activation threshold, thereby rendering T cells less sensitive to stimulation. Signif icantly, the data demonstrate hierarchical sensitivity of selected cytokine responses to PP14-mediated inhibition, with the hierarchy reflecting their respective activation thresholds. These findings suggest a novel paradigm for immunoinhibition wherein negative regulators can finely tune, rather th an inactivate, T-cell responses, and thereby skew the cytokine output of im munologic responses. (C) 2001 by The American Society of Hematology.