Abstract
Selective clonal deletion in the CD4+ T cell compartment during the transition from effector to memory is accompanied by enhanced expression of the pro-apoptotic Bcl-2 family member Bim. Here, we show that Bim deficiency enables the survival of poorly functional Th1 responders that are normally eliminated during contraction. However, rescued bim −/− CD4+ “memory” T cells continued to demonstrate deficient effector functions, poor sensitivity to antigen and an inability to respond to secondary challenge. Our results demonstrate that Bim activity plays a key role in shaping the CD4+ memory T cell repertoire, ensuring the emergence of highly functional CD4+ memory T cells and the elimination of Th1 effector cells with sub-optimal function. We propose that Bim is a key mediator of T cell death in the absence of appropriate TCR-driven activation and differentiation.
Highlights
Following acute viral or bacterial infection, antigen-specific T cells clonally expand and acquire effector functions that contribute to pathogen clearance
Bim Expression is Upregulated in LCMV GP61–80 epitope (Lm-gp61)-induced SMARTA Effector Th1 Cells
We previously found that SMARTA effector Th1 cells generated following Lm-gp61 infection expressed higher levels of Bim mRNA transcripts at the peak of their response compared to SMARTA effector Th1 cells induced by lymphocytic choriomeningitis virus (LCMV) infection
Summary
Following acute viral or bacterial infection, antigen-specific T cells clonally expand and acquire effector functions that contribute to pathogen clearance. Following elimination of the pathogen, 90– 95% of effector T cells die, leaving behind a long-lived pool of memory T cells. CD4+ T cells, on the other hand, require several days of in vivo antigen exposure to achieve maximal expansion and differentiation into pathogen-specific effector cells [6,7,8]. These observations suggest that CD4+ T cells translate TCR signals into a downstream activation/differentiation program in a fundamentally different fashion than do CD8+ T cells. The requirement for prolonged exposure to antigen suggests that CD4+ T cell differentiation and survival may be prone to selection on the basis of qualitative and/or quantitative components of the antigen signal [9,10,11]
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