Role of STAT4 and STAT6 signaling in allograft rejection and CTLA4-Ig-mediated tolerance

Citation
P. Zhou et al., Role of STAT4 and STAT6 signaling in allograft rejection and CTLA4-Ig-mediated tolerance, J IMMUNOL, 165(10), 2000, pp. 5580-5587
Citations number
38
Categorie Soggetti
Immunology
Journal title
JOURNAL OF IMMUNOLOGY
ISSN journal
00221767 → ACNP
Volume
165
Issue
10
Year of publication
2000
Pages
5580 - 5587
Database
ISI
SICI code
0022-1767(20001115)165:10<5580:ROSASS>2.0.ZU;2-M
Abstract
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.