Allopeptide-specific CD4+ T cells facilitate the differentiation of directly alloreactive graft-infiltrating CD8+ T cells

Abstract

To investigate the mechanism of CD4+ T-cell help during the activation and differentiation of directly alloreactive CD8+ T cells, we examined the development of obliterative airways disease (OAD) following transplantation of airways into fully mismatched recipient mice deficient in CD4+ T cells. BALB/c trachea allografts became fibrosed significantly less frequently in B6 CD4-/- recipients as compared to wildtype controls. Furthermore, class I-directed cytotoxicity failed to develop in the absence of CD4+ T cells. The infiltration of graft tissue by primed Ld-specific directly alloreactive 2C CD8+ T cells was not found to depend on the presence of CD4+ T cells. Nevertheless, graft-infiltrating 2C CD8+ T cells failed to express CD69 and granzyme B when CD4+ T-cell help was unavailable. Importantly, reconstitution of B6 CD4-/- recipient mice with graft peptide-specific TCR-Tg CD4+ T cells (OT-II or TEa) capable of recognizing antigen only on recipient APC allowed for full expression of CD69 and granzyme B by the directly alloreactive CD8+ T cells and restored the capacity of recipients to reject their allografts. These results demonstrate that indirectly alloreactive CD4+ T cells ensure the optimal activation and differentiation of graft-infiltrating directly alloreactive CD8+ T cells independent of donor APC recognition. © 2007 The Authors.