CD4(+) T cell-mediated protection against a lethal outcome of systemic infection with vesicular stomatitis virus requires CD40 ligand expression, butnot IFN-gamma or IL-4

To investigate the mechanism(s) whereby T cells protect against a lethal ou tcome of systemic infection with vesicular stomatitis virus, mice with targ eted defects in genes central to T cell function were tested for resistance to i.v. infection with this virus. Our results show that mice lacking the capacity to secrete both IFN-gamma and perforin completely resisted disease . Similar results were obtained using IL-4 knockout mice, indicating that n either cell-mediated nor T(h)2-dependent effector systems were required. In contrast, mice deficient in expression of CD40 ligand were more susceptibl e than wild-type mice, and residual resistance in these mice was almost com pletely abrogated by depletion of CD8(+) T cells. In keeping with this, mic e lacking both MHC class I and class II expression succumbed to the infecti on, whereas most class II-deficient mice normally survive. Adoptive transfe r experiments using B cell- and T cell-deficient recipients revealed that n o protection could be obtained in the absence of B cells, whereas treatment with virus-specific immune (IgG) serum controlled viral spreading to the c entral nervous system (CNS), but did not necessarily accomplish virus elimi nation. Taken together, these results underscore that B cells are essential in preventing early infection of the CNS, but T cells are required for lon g-term survival. CD4(+) T cells are most efficient in this context and the key function is to provide cognate help to B cells. However, if CD4(+) cell function is compromised, CD8(+) T cells become critical and may suffice fo r survival.