Role of tumor necrosis factor receptors in regulating CD8 T-Cell responses during acute lymphocytic choriomeningitis virus infection

The role of tumor necrosis factor (TNF) in regulating various phases of the antiviral T-cell response is incompletely understood. Additionally, despite strong evidence ascribing a role for TNF in protecting against T-cell-dependent autoimmunity, the underlying mechanisms are still obscure. To address these issues, we have investigated the role of tumor necrosis factor receptors (TNFRs) I (p55R) and II (p75R) in regulating CD8 T-cell responses to lymphocytic choriomeningitis virus (LCNW) with wild-type, p55R-deficient (p55(-/-)), p75R-deficient (p75(-/-)), and p55R- and p75R-deficient (DKO) mice. Loss of p55R increased the number of memory CD8 T cells to only one of the two immunodominant epitopes, and p75R deficiency had a minimal impact on the T-cell response to LCW. Strikingly, deficiency of both p55R and p75R had a more dramatic effect on the LCW-specific CD8 T-cell response; in the DKO mice, as a sequel to enhanced expansion and a reduction in contraction of CD8 T cells, there was a substantial increase in the number of memory CD8 T cells (specific to the two immunodominant epitopes). While the majority of LCW-specific memory CD8 T cells in wild-type mice were CD62L(hi) CCR7(hi) (central memory), a major proportion of memory CD8 T cells in DKO mice were CD62L(lo) CCR7(hi). TNFR deficiency did not affect the proliferative renewal of memory CD8 T cells. Taken together, these data suggested that TNFRs p55R and p75R have overlapping roles in downregulating CD8 T-cell responses and establishment of immune homeostasis during an acute viral infection.