| Abstract | Fas death pathway is important for lymphocyte homeostasis, but the role of Fas pathway in T cell memory development is not clear. We show that whereas the expansion and contraction of CD8+ T cell response against Listeria monocytogenes were similar for wild-type (WT) and Fas ligand (FasL) mutant mice, the majority of memory CD8+ T cells in FasL mutant mice displayed an effector memory phenotype in the long-term in comparison with the mainly central memory phenotype displayed by memory CD8+ T cells in WT mice. Memory CD8+ T cells in FasL mutant mice expressed reduced levels of IFN-γ and displayed poor homeostatic and Ag-induced proliferation. Impairment in CD8+ T cell memory in FasL mutant hosts was not due to defective programming or the expression of mutant FasL on CD8+ T cells, but was caused by perturbed cytokine environment in FasL mutant mice. Although adoptively transferred WT memory CD8+ T cells mediated protection against L. monocytogenes in either the WT or FasL mutant hosts, FasL mutant memory CD8+ T cells failed to mediate protection even in WT hosts. Thus, in individuals with mutation in Fas pathway, impairment in the function of the memory CD8+ T cells may increase their susceptibility to recurrent/latent infections. The importance of T cell memory for the control of intracellular pathogens is well documented (1, 2, 3); however, the mechanisms that govern the induction and maintenance of memory T cells are not clear. During T cell priming, CD8+ T cells undergo massive proliferation (>1000-fold), which is followed by a contraction phase wherein the majority (>90%) of activated cells die by apoptosis (4). Engagement of Fas, with its ligand (FasL),3 is thought to play a key role in the regulation of T cells (5, 6) because the interaction between activated T cells expressing Fas and FasL provides a mechanism for deleting T cells. This view is supported by the observation that lpr mice that bear mutation in Fas gene develop lymphadenopathy (7), and T cells from lpr mice are resistant to activation-induced cell death (8, 9, 10). Furthermore, T cell tolerance induction to superantigen is impaired or delayed in lpr mice (11, 12, 13, 14). The role of Fas in regulating CD8+ T cell homeostasis has been controversial because autoreactive CD8+ T cells induced by cross-presentation of self Ags are deleted by a Fas-dependent mechanism (15), whereas the expansion and contraction of Ag-specific CD8+ T cell response induced after viral infection in vivo have been shown to occur by Fas-independent mechanisms (16, 17). We evaluated the development and maintenance of OVA-specific CD8+ T cells in normal and FasL mutant mice using recombinant intracellular bacterium, Listeria monocytogenes (LM)-expressing OVA as an immunogen. Our results reveal that although the expansion and contraction of CD8+ T cell response proceed normally in FasL mutant mice, memory CD8+ T cells in FasL mutant mice display a skewed phenotype and poor homeostatic proliferation and fail to mediate effective protection against pathogen rechallenge. |
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