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Allograft Rejection Requires STAT5a/b-Regulated Antiapoptotic Activity in T Cells but Not B Cells¹

Ye Zhang^*, Robert A. Kirken, Lucrezia Furian^*, Slawa Janczewska^*, Xiumei Qu^*, Wayne W. Hancock, Mouer Wang^*, Neelam Tejpal^*, Ronald Kerman^*, Barry D. Kahan^* and Stanislaw M. Stepkowski^2,*

^* Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Medical School, Houston, TX 77030; Department of Biological Sciences, University of Texas, El Paso, TX 79968; and Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA 19104

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- mRNA; ELISPOT assay showed an equivalent number of IL-4- and IFN--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.