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Role of STAT4 and STAT6 Signaling in Allograft Rejection and CTLA4-Ig-Mediated Tolerance¹

Ping Zhou^*, Greg L. Szot, Zhong Guo^*, Oliver Kim, Gang He^*, Jun Wang^*, Michael J. Grusby, Kenneth A. Newell^*, J. Richard Thistlethwaite^*, Jeffrey A. Bluestone^2, and Maria-Luisa Alegre^2,

Section of Transplantation, Departments of ^* Surgery and Pathology, and Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL 60637

STAT4^-/- mice have impaired type 1 T cell differentiation, whereas STAT6^-/- mice fail to generate type 2 responses. The role of type 1 and type 2 T cell differentiation in acute cardiac allograft rejection and in the induction of tolerance was examined in wild-type, STAT4^-/-, and STAT6^-/- recipients. All recipients rejected the grafts promptly. Analysis of in situ cytokine gene expression in the allografts confirmed decreased levels of IFN- in STAT4^-/- recipients and undetectable levels of IL-4 and IL-5 in STAT6^-/- mice. Blockade of the CD28/B7 costimulatory pathway prolonged cardiac graft survival for >100 days in 100% of wild-type and STAT4^-/- mice. However, 14% of CTLA4-Ig-treated STAT6^-/- mice rejected their grafts between 20 and 100 days. Moreover, of those animals followed past 100 days, 60% of the STAT6^-/- mice rejected their grafts. Splenocytes harvested on day 145 posttransplant from CTLA4-Ig-treated rejecting STAT6^-/- recipients were transfused into syngeneic SCID mice transplanted with donor or third party cardiac allografts. Both donor and third party grafts were rejected, indicating that the initial graft loss may be due to an immunological rejection. In contrast, when splenocytes from CTLA4-Ig-treated wild-type or nonrejecting STAT6^-/- mice were transferred into SCID recipients, donor allografts were accepted, but third party hearts were rejected. Thus, long-term prolongation of cardiac allograft survival by CTLA4-Ig is STAT4-independent but, at least in part, STAT6-dependent. These data suggest that the balance of type 1 and type 2 T lymphocyte differentiation is not critical for acute rejection but influences the robust tolerance induced by CD28/B7 blockade in this model.