Aggressive skin allograft rejection in CD28(-)/(-) mice independent of theCD40/CD40L costimulatory pathway

CD28(-/-) mice have been utilized to study the role of B7/CD28 and B7-CTLA4 interactions. There is evidence that CTLA4 ligation may be critical for to lerance induction. The aim of the current study is to further investigate r ejection responses of CD28(-/-) mice and to define the role of B7-CTLA4 int eractions in the absence of the CD40 and CD28 pathways. Balb/c skin allogra fts were transplanted onto C57BL/6 (B6) wild type or CD28(-/-) mice treated with anti-CD40L, CTLA4-Ig, or combination blockade. To investigate the cel lular mechanism of rejection in CD28(-/-) recipients, mice were treated wit h anti-CD4 or anti-CD8 antibodies prior to treatment with costimulation blo ckade. The fluoroscein dye USE was utilized to study T cell expansion in vi vo. Surprisingly, treatment of B6 CD28(-/-) mice with CTLA4-Ig alone (MST 1 2d), anti-CD40L alone (MST 13d), or combined blockade (MST 13d) had no effe ct on allograft survival compared to untreated B6 CD28(-/-) mice (MST lid). CD28(-/-) recipients depleted of CD4(+) cells and treated with CTLA4-Ig, a nti-CD40L, or combination blockade also did not have prolonged survival com pared with untreated mice (MST 10d). In contrast, CD28(-/-) recipients depl eted of CD8(+) cells had markedly prolonged allograft survival when treated with either anti-CD40L alone (MST 49d) or with combination blockade (MST 5 7d). Studies utilizing USE demonstrated that CD28(-/-) CD8(+) T cells are n ot defective in in vivo proliferation responses compared with wild type CD8 cells. Thus, CD28(-/-) CD8(+) T cells are responsible for aggressive rejec tion responses of CD28(-/-) mice independent of the CD40 pathway. In additi on, CD40L blockade does not result in CD4(+) T cell tolerance in CD28(-/-) recipients, despite an intact B7-CTLA4 pathway. (C) 2001 Elsevier Science B .V. All rights reserved.