Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins.

After an acute infection, most effector T cells die, whereas some remain and become a stable memory population. Over recent years, progress has been made in our understanding of this cell fate decision. For example, the effector population is heterogeneous, loosely identified by reciprocal expression of Killer cell lectin-like receptor G1 (KLRG1) and IL-7 Rα (CD127). Adoptive transfer of KLRG1loCD127hi cells results in better survival and memory generation compared with their KLRG1hiCD127lo counterparts.1 These effector T-cell subsets are driven by distinct networks: a transcriptional program involving Blimp1, Id2 and t-bet is critical for the generation of KLRG1hiCD127lo effector cells,1, 2, 3, 4 whereas an alternative transcriptional program involving Bcl-6, STAT3, eomoesodermin, Id3 and T-cell factor-1 are critical for the generation of KLRG1loCD127hi pre-memory cells.5, 6, 7, 8, 9, 10 Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, the results are complicated by the fact that little work has been done examining effector CD8+ T-cell responses in mice whose death programs have been disabled. Although the extrinsic cell death pathway was initially thought to control contraction of T-cell responses, our and others data show a dominant role for the Bcl-2-regulated pathway. Germline deletion of the pro-apoptotic Bcl-2 family member, Bim, enhances CD4+ and CD8+ T-cell responses to viral, bacterial and parasitic infection.11, 12, 13, 14 One report suggested a minor role for another Bcl-2 homology domain 3 (BH3)-only Bcl-2 family member, Puma, although the role of Puma on effector T-cell subsets was not examined.15 Noxa has a marginal role in contraction of T-cell responses.16, 17 Although Bim is the most dominant pro-apoptotic Bcl-2 family member driving contraction of T-cell responses, the study of T-cell responses to acute infection in Bim−/− mice is complicated by the ongoing autoimmune disease and altered negative selection in these mice.18 Further, other data suggest that dendritic cell (DC) expression of Bim can control the magnitude of T-cell responses.19 Thus, the cell-specific roles of Bim and the potential contributions of other pro-apoptotic Bcl-2 family members remain unclear. Here, we report that T-cell-specific deletion of Bim recapitulated the effects of germline loss of Bim on the contraction of T-cell responses in vivo. Although Bim was critical to limit survival of KLRG1hiCD127lo cells at earlier phases after infection, the absence of Bim enriched for KLRG1loCD127hi cells as the response progressed. This later loss of KLRG1hiCD127lo cells was due to the increased competition for IL-15 as a result of massive accumulation of effector T cells in Bim-deficient environment. The combined loss of Bim and Puma or Bim and Noxa, significantly reduced contraction of CD8+ T-cell responses compared with single-deficient mice. Together, our data show that effector T cells are kept in check first by Bim and then by limiting amounts of IL-15 (and likely other nutrients), which in turn trigger other BH3-only proteins.