Allograft rejection requires STAT5a/b-regulated antiapoptotic activity in T cells but not B cells

STATs play key roles in immune function. We examined the role of STAT5a/b in allograft rejection. STAT5a/b-deficient mice showed a 4-fold increased survival time of heart allografts (p < 0.01). Unlike wild type, purified STAT5a/b-/- T cells transferred to Rag1-/- recipients failed to mediate heart allograft rejection until supplemented with STAT5a/b-/- B cells. In vitro, STAT5a/b-/- T cells did not proliferate in response to Con A or alloantigens but entered apoptosis within 48 h (95%). Activated STAT5a/b-/- T cells showed increased expression of proapoptotic (caspases, DNA repair genes, TNF/TNFR-associated factor family genes) and decreased antiapoptotic mRNAs in microarrays, while Western blots confirmed reduced antiapoptotic Bcl-2 and elevated proapoptotic Bax protein expression. Interestingly, at 24 h postactivation, STAT5a/b+/+ and STAT5a/b-/- T cells produced similar levels of IL-2, IL-4, IL-10, and IFN-gamma mRNA; ELISPOT assay showed an equivalent number of IL-4- and IFN-gamma-producing T cells in both STAT5a/b+/+ and STAT5a/b-/- splenic populations. Sera from STAT5a/b+/+ and STAT5a/b-/- rejectors had donor-specific IgM, IgG1, IgG2a, and IgG2b Ab, while STAT5a/b deficiency had no impact on B cell survival or proliferation in response to LPS. Compared with allografts from STAT5a/b+/+ recipients, heart allografts from STAT5a/b-/- recipients had markedly reduced infiltration by CD4 and CD8 T cells but increased infiltration by B cells and dense endothelial deposition of C4d, a marker of humoral rejection. Thus, activated STAT5a/b-/- T cells produce cytokines prior to entering apoptosis, thereby promoting differentiation of B cells yielding donor-specific IgM and IgG Ab that mediate allograft rejection.     

SHP-1 regulates STAT6 phosphorylation and IL-4-mediated function in a cell type-specific manner

SHP-1 has been shown to play positive and negative regulatory roles in IL-4-induced STAT6 phosphorylation and in IL-4-mediated functions. To determine whether SHP-1 can regulate STAT6 phosphorylation and IL-4-mediated functions in a cell type-specific manner in the immune system, we examined the IL-4 receptor (IL-4R) expression, STAT6 phosphorylation, and IL-4-mediated functions in CD4+ and CD8+ T cells of viable motheaten (me(v)/me(v)) and littermate control (+/-) mice. CD4+ T cells as well as CD8+ T cells from the lymph node of me(v)/me(v) and +/- mice expressed comparable levels of IL-4R. In CD4+ T cells, the loss of SHP-1 activity did not affect IL-4-induced STAT6 phosphorylation or IL-4-mediated function. In contrast, SHP-1-deficient CD8+ T cells from me(v)/me(v) mice failed to develop into IL-4-producing type-2 cytotoxic T cells (Tc2) in the presence of IL-4 despite that they showed comparable levels of STAT6 phosphorylation to that of +/- CD8+ T cells. Loss of SHP-1 activity also abolished IL-4-mediated inhibition of c-kit expression in bone marrow-derived mast cell (BMMC). Thus, our data suggest that SHP-1 may regulate IL-4-induced STAT6 phosphorylation and IL-4-mediated functions in a cell type-specific manner.