Role of CD40 ligand and CD28 in induction and maintenance of antiviral CD8(+) effector T cell responses

The primary aim of this report was to evaluate the immune responses of CD40 ligand-deficient (CD40L(-/-)) mice infected with two viruses known to diff er markedly in their capacity to replicate in the host. Lymphocytic choriom eningitis virus (LCMV) is a natural mouse pathogen that replicates widely a nd extensively, whereas vesicular stomatitis virus (VSV) spreads poorly. We found that the primary response of CD40L(-/-) mice toward VSV is significa ntly impaired; proliferation of both CD4(+) and CD8(+) cells is reduced 2- to 3-fold, few CD8(+) cells acquire an activated phenotype, and little func tional activity is induced. Very similar results were obtained in VSV-infec ted, CD28-deficient mice. In contrast, neither CD40L nor CD28 was required for induction of a primary CD8(+) response toward LCMV, Surprisingly, lack of CD4(+) T cells had no impact on the primary immune response toward any o f the viruses, even though the CD40 ligand dependence demonstrated for VSV would be expected to be associated with CD4 dependence. Upon coinfection of VSV-infected mice with LCMV, the requirement for CD40 ligand (but not CD28 ) could be partially bypassed, as evidenced by a 3-fold increase in the fre quency of VSV specific CD8(+) T cells on day 6 postinfection, Finally, desp ite the fact that the primary LCMV-specific CDS' response is virtually unim paired in CD40L(-/-) mice, their capacity to maintain CD8(+) effector activ ity and to permanently control the infection is significantly reduced. Thus , our results demonstrate that the importance of CD40/CD40L interaction for activation of CD8(+) T cells varies between viruses and over time.