Indirect regulation of CD4 T-cell responses by tumor necrosis factor receptors in an acute viral infection.

Despite the well-recognized importance of CD4 T-cell help in the induction of antibody production and cytotoxic-T-lymphocyte responses, the regulation of CD4 T-cell responses is not well understood. Using mice deficient for TNF receptor I (TNFR I) and/or TNFR II, we show that TNFR I and TNFR II play redundant roles in down regulating the expansion of CD4 T cells during an acute infection of mice with lymphocytic choriomeningitis virus (LCMV). Adoptive transfer experiments using T-cell-receptor transgenic CD4 T cells and studies with mixed bone marrow chimeras indicated that indirect effects and not direct effects on T cells mediated the suppressive function of TNF on CD4 T-cell expansion during the primary response. Further studies to characterize the indirect effects of TNF suggested a role for TNFRs in LCMV-induced deletion of CD11c(hi) dendritic cells in the spleen, which might be a mechanism to limit the duration of antigenic stimulation and CD4 T-cell expansion. Consequent to enhanced primary expansion, there was a substantial increase in the number of LCMV-specific memory CD4 T cells in the spleens of mice deficient for both TNFR I and TNFR II. In summary, our findings suggest that TNFRs down regulate CD4 T-cell responses during an acute LCMV infection by a non-T-cell autonomous mechanism.