Bcl-2 Allows Effector and Memory CD8+ T Cells To Tolerate Higher Expression of Bim

Abstract

As acute infections resolve, most effector CD8+ T cells die, whereas some persist and become memory T cells. Recent work showed that subsets of effector CD8+ T cells, identified by reciprocal expression of killer cell lectin-like receptor G1 (KLRG1) and CD127, have different lifespans. Similar to previous reports, we found that effector CD8+ T cells reported to have a longer lifespan (i.e., KLRG1lowCD127high) have increased levels of Bcl-2 compared with their shorter-lived KLRG1highCD127low counterparts. Surprisingly, we found that these effector KLRG1lowCD127high CD8+ T cells also had increased levels of Bim compared with KLRG1highCD127low cells. Similar effects were observed in memory cells, in which CD8+ central memory T cells expressed higher levels of Bim and Bcl-2 than did CD8+ effector memory T cells. Using both pharmacologic and genetic approaches, we found that survival of both subsets of effector and memory CD8+ T cells required Bcl-2 to combat the proapoptotic activity of Bim. Interestingly, inhibition or absence of Bcl-2 led to significantly decreased expression of Bim in surviving effector and memory T cells. In addition, manipulation of Bcl-2 levels by IL-7 or IL-15 also affected expression of Bim in effector CD8+ T cells. Finally, we found that Bim levels were significantly increased in effector CD8+ T cells lacking Bax and Bak. Together, these data indicate that cells having the highest levels of Bim are selected against during contraction of the response and that Bcl-2 determines the level of Bim that effector and memory T cells can tolerate.

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

“…34 Such IL-15 limitation likely enhances Puma expression in KLRG1 hi CD127 lo cells relative to KLRG1 lo CD127 hi cells as the latter cells can utilize both IL-7 and IL-15 for survival. 33 Further, we confirm and extend prior results, showing that Puma has a preferential effect on contraction of KLRG1 hi CD127 lo cells. 15 Thus, in the absence of Bim, the enormous numbers of KLRG1 hi CD127 lo cells act as a sink for IL-15 and likely other nutrients (glucose, amino acids) that prevent engagement of other BH3-only proteins.…”

“…1,32-34 IL-15 is critical for maintaining expression of Bcl-2, a major Bim antagonist in effector CD8 þ T cells. 33 The huge size of the anti-LCMV CD8 þ T-cell response, even in WT mice, likely limits the effector response by restricting IL-15 availability. 34 Such IL-15 limitation likely enhances Puma expression in KLRG1 hi CD127 lo cells relative to KLRG1 lo CD127 hi cells as the latter cells can utilize both IL-7 and IL-15 for survival.…”

“…Second, the absence of Bim may protect KLRG1 lo CD127 hi cells from death as many of these cells die in WT mice. 1,14,33 KLRG1 lo CD127 hi cells are more protected from death because they express increased levels of Bcl-2, as genetic loss or pharmacologic inhibition of Bcl-2 enhanced their Bimdriven death. 33,43 Further, we have shown that a common g chain cytokine/STAT5/Bcl-2 network acts downstream of IL-7 and IL-15 to protect KLRG1 lo CD127 hi effector T cells from Bim and likely Puma, favoring memory cell development.…”

“…1,14,33 KLRG1 lo CD127 hi cells are more protected from death because they express increased levels of Bcl-2, as genetic loss or pharmacologic inhibition of Bcl-2 enhanced their Bimdriven death. 33,43 Further, we have shown that a common g chain cytokine/STAT5/Bcl-2 network acts downstream of IL-7 and IL-15 to protect KLRG1 lo CD127 hi effector T cells from Bim and likely Puma, favoring memory cell development. 34 Third, as mentioned above, the massive expansion of effector and pre-memory subsets in Bim À / À mice severely restricts IL-15 availability for KLRG1 hi CD127 lo cells.…”

Mcl-1 antagonizes Bax/Bak to promote effector CD4+ and CD8+ T-cell responses

“…7,8 Indeed, the BH3-only molecule Bim, acting through Bax/Bak, is required for the apoptosis of most effector T cells. 2,[9][10][11][12][13] Genetic ablation of Bim prevents the loss of effector CD4 þ and CD8…”