Rebres et al. have demonstrated that SIRP-��-Fc ligation synergizes with CD3 for T cell activation and induces PKC �� translocation, resulting in IL-2 production by T cells [19]. DCs, through autocrine secretion of IL-2, trans-present IL-2 to T cells for optimal clonal expansion no and effector function [39]. Thus, in addition to T cell-derived IL-2, DCs also could reverse a CD47low to a CD47high status. We showed here that a CD47high status was maintained on CD4 effectors in inflamed CD tissues. This suggests that auto-aggressive T cells that contribute to tissue destruction, might possess a deregulation in the conformational change process of CD47 which is revealed by an increase in SIRP-��-Fc binding. CD47high status confers resistance to TSP-1-induced killing to CD4 tissue effectors that accumulate in tissues, as we observed abundant TSP-1 release in CD tissues.

In that regard, we recently reported that CD47high status on CD4 effectors identifies functional long-lived memory T cell progenitors [16]. Therefore, maintenance of a CD47high status in pathology may be deleterious to the host and perpetuate chronic inflammatory response. How effector T cell death is regulated during the contraction phase is not fully understood. For many years, the Fas death receptor was considered to be the only T cell surface molecule implicated in the contraction phase of the IR. Fas-mediated signaling leads to activation-induced caspase-dependent apoptosis of TCR-expanded T cells [40], [41]. Mice lacking functional genes for Fas or its ligand (FasL), show uncontrolled lympho-proliferation and developed autoimmunity [42], [43].

CD47 has been linked to Fas [44]. Yet, CD47?/? mice do not display lympho-proliferative disorders as seen in Fas-deficient mice [45]. Fas signaling, like CD47, kills TEM cells and spares TCM as well as TN cells. However, unlike differential CD47 status, Fas expression is similar on TEM and TCM cell subsets [46]. CD47 augments Fas-mediated apoptosis, but CD47-initiated signaling is not required to enable Fas killing. This process is unidirectional since Fas is not necessary for CD47-mediated killing [44]. We thus propose that CD47, rather than Fas-mediated cell death, plays a key role in the dampening of an acute response. We showed here an increased yield of Ag-specific CD47?/? T cells in CD47?/? hosts while Ag-specific CD47+/+ T cell were barely detectable 70 days after primary immunization.

In Drug_discovery fact, the role of Fas in contraction phase has been challenged by Alexander et al, who showed that the elimination of effector T cells is completely independent of caspase activation. Administration of 11 different regimens of a pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-?uoromethylketone (zVAD) in vivo showed no significant impact on effector or memory CD8 or CD4 T cell development [4].