Published online before print August 17, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0407240

Received for publication April 23, 2007.
Revised July 24, 2007.
Accepted for publication July 24, 2007.

Article

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

Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA

^@ To whom correspondence should be addressed. E-mail: sureshm{at}svm.vetmed.wisc.edu.

Abstract

It is known that TNF- (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 show further that attenuation of effector cell apoptosis induced by TNF deficiency (TNF–/–) 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–/– mice was not associated with up-regulation of IL-7R 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.

Key Words: homeostasis • virus • apoptosis • immunity • proliferation

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