Preapoptotic Phenotype of Viral Epitope-Specific CD8 T Cells Precludes Memory Development and Is an Intrinsic Property of the Epitope

Abstract

Virus-specific CD8 T cells after clearance of infection reduce their number in lymphoid organs by apoptotic death and by migration into peripheral tissues. During and after infection, many lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells in lymphoid but not peripheral tissues are in a preapoptotic state, as detected by the early apoptosis marker annexin V. In this report, we investigated the significance of this preapoptotic state and how it may be influenced by viral epitope specificity. Stimulation with anti-CD3 or IL-2 in vitro postponed DNA fragmentation in annexin V+ cells, but adoptive transfer studies in vivo showed that this preapoptotic phenotype precluded the development of functional memory. CD8 T cells specific to LCMV epitopes NP396 and gp33 differed in their preapoptotic state, with NP396-specific T cells binding more annexin V than gp33-specific T cells. These epitope- and tissue-dependent differences were seen in primary, memory, and secondary responses and in mice receiving different displays of Ag by infection with LCMV strains of different tropisms or by infection with vaccinia virus recombinants expressing LCMV proteins. Thus, the epitope-dependent differences in apoptosis were independent of virus tropisms, duration of Ag exposure, and competition within APCs, and were an intrinsic property of the epitope. The tissue-dependent and epitope-dependent preapoptotic state correlated with reduced expression of IL-7Rα.

CD40 on APCs Is Needed for Optimal Programming, Maintenance, and Recall of CD8+ T Cell Memory Even in the Absence of CD4+ T Cell Help

“…2A and data not shown). This is consistent with a previous study of LCMV infection showing similarly high levels of annexin V staining in virusspecific CD8 ϩ T cells (48). In comparing the T cells in WT and CD40…”

IL-15 Regulates CD8+ T Cell Contraction during Primary Infection

“…Becker et al (21) have reported that the CD8 ϩ T cell responses to most of epitopes, including NP396, were only slightly, if any, affected after primary infection, whereas CD8 ϩ T cell response to one epitope (GP33) did show a rather dramatic requirement for IL-15. Wang et al (35) showed that CD8 ϩ T cells specific to LCMV epitopes NP396 and GP33 differed in their preapoptotic state, with NP396-specific T cells binding more annexin V than GP33-specifc T cells during the expansion phase on day 8 after LCMV infection. These results suggest that population of T cells specific to different epitopes can have different properties such as IL-15 dependency during the expansion phase after acute infection.…”

To kill or be killed: how HIV exhausts the immune system

“…In the LCMV murine model, many virus-specific CD8 T cells in lymphoid organs are in a preapoptotic state (Annexin-V þ ), which was shown to preclude the development of functional memory. 136 In HIV infection, downregulation of Bcl-2 and Bcl-x L was detected on peripheral blood 93,95 and lymph node CD8 T cells, 94 priming these cells for autonomous cell death, 93 and contributing to the deletion of HIV-specific memory T cells. 95 Bcl-2 downregulation and CTL apoptosis may also be induced by high doses of virus during the primary viral infection, causing the rapid deletion of high avidity virus-specific CTLs, as suggested in a murine model.…”