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 Ragl-/- 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 Immoral 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.