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 indu
ction of tolerance was examined in wild-type, STAT4(-/-), and STAT6(-/-) re
cipients. All recipients rejected the grafts promptly, Analysis of in situ
cytokine gene expression in the allografts confirmed decreased levels of IF
N-gamma in STAT4(-/-) recipients and undetectable levels of IL-4 and IL-5 i
n STAT6-/- mice. Blockade of the CD28/B7 costimulatory pathway prolonged ca
rdiac graft survival for > 100 days in 100% of wild-type and STAT4(-/-) mic
e. However, 14% of CTLA4-Ig-treated STAT6(-/-) mice rejected their grafts b
etween 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(-/-) recipient
s 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 reje
ction. In contrast, when splenocytes from CTLA4-Ig-treated wild-type or non
rejecting STAT6(-/-) mice were transferred into SCID recipients, donor allo
grafts were accepted, but third party hearts were rejected. Thus, long-term
prolongation of cardiac allograft survival by CTLA4-Ig is STAT1-independen
t but, at least in part, STAT6-dependent, These data suggest that the balan
ce of type 1 and type 2 T lymphocyte differentiation Is not critical for ac
ute rejection but influences the robust tolerance induced by CD28/B7 blocka
de in this model.