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

Abstract: It is known that TNF- (TNF) exerts distinct tissue-protective or-destructive effects in the pathogenesis of T cell-dependent immunopa-thology, depending on the context and amount of cytokine produced. To better understand the cel-lular 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 choriomenin-gitis 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 prolifer-ation of effector cells in vivo. We show further that attenuation of effector cell apoptosis induced by TNF deficiency (TNF–/–) led to a substantial in-crease 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–/ – mice was not associated with up-regulation of IL-7R or Bcl-2 in effector cells, which indicated that TNF might limit differentia-tion of memory cells from IL-7Rlo effector cells. Collectively, these data are strongly suggestive of a role for TNF in down-regulating CD8 T cell re-sponses and the establishment of CD8 T cell mem-ory 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