A role for TNF in limiting the duration of CTL effector phase and magnitude of CD8 T cell memory.

It is known that TNF-alpha (TNF) exerts distinct tissue-protective or -destructive effects in the pathogenesis of T cell-dependent immunopathology, depending on the context and amount of cytokine produced. To better understand the cellular mechanisms underlying the regulation of T cells by TNF, we have analyzed the role of TNF in regulating various facets of the antigen-specific CD8 T cell response to lymphocytic choriomeningitis virus (LCMV) in mice. We show that expansion and differentiation of virus-specific effector CD8 T cells and LCMV clearance are not dependent on TNF. Instead, we demonstrate that TNF limits the duration of the effector phase of the CD8 T cell response by regulating apoptosis and not proliferation of effector cells in vivo. We further show that attenuation of effector cell apoptosis induced by TNF deficiency led to a substantial increase in the number of virus-specific memory CD8 T cells without affecting their function. The enhancement in the number of memory CD8 T cells in TNF-deficient (TNF-/-) mice was not associated with up-regulation of IL-7Ralpha or Bcl-2 in effector cells, which indicated that TNF might limit differentiation of memory cells from IL-7R(lo) effector cells. Collectively, these data are strongly suggestive of a role for TNF in down-regulating CD8 T cell responses and the establishment of CD8 T cell memory during an acute viral infection. These findings further our understanding of the regulation of CD8 T cell homeostasis and have implications in vaccine development and clinical use of anti-TNF therapies to treat T cell-dependent, inflammatory disorders.