Inflammation Directs Memory Precursor and Short-Lived Effector CD8+ T Cell Fates via the Graded Expression of T-bet Transcription Factor

Abstract

As acute infections resolve, effector CD8(+) T cells differentiate into interleukin-7 receptor(lo) (IL-7R(lo)) short-lived effector cells (SLECs) and IL-7R(hi) memory precursor effector cells (MPECs) capable of generating long-lived memory CD8(+) T cells. By using another SLEC marker, KLRG1, we found that KLRG1(hi) effector cells began appearing early during infection and were committed to downregulating IL-7R. Unlike IL-7R(hi) MPECs, KLRG1(hi) IL-7R(lo) SLECs relied on IL-15, but IL-15 could not sustain their long-term maintenance or homeostatic turnover. The decision between SLEC and MPEC fates was regulated by the amount of inflammatory cytokines (i.e., IL-12) present during T cell priming. According to the amount of inflammation, a gradient of T-bet was created in which high T-bet expression induced SLECs and low expression promoted MPECs. These results elucidate a mechanism by which the innate immune system sets the relative amounts of a lineage-determining transcription factor in activated CD8(+) T cells and, correspondingly, regulates their memory cell potential.

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

“…Although suggested in a prior study, transfers of purified populations of effector subsets were not performed making it difficult to determine whether conversion had occurred. 12 However, in other work, transferred WT KLRG1 hi cells did not revert to KLRG1 lo cells; 1,41,42 and here the numbers of KLRG1 lo CD127 hi cells in Bim À / À mice did not increase in proportion to the loss of KLRG1 hi C-D127 lo cells, arguing against conversion. More work is needed to determine if, in the absence of death, some KLRG1 hi CD127 lo cells convert to KLRG1 lo CD127 hi cells.…”

“…The differentiation of effector T-cell subsets is controlled by the cytokine milieu, pro-inflammatory cytokines direct the differentiation of KLRG1 hi CD127 lo cells, whereas IL-10 and IL-21 guide the differentiation of KLRG1 lo CD127 hi cells. 1,7 No difference in the levels of serum IL-10 between WT and Bim À / À mice was observed at several time points (unpublished data). To determine whether the effects of Bim on subset differentiation were T-cell intrinsic, we adoptively transferred small 20 and infected with LCMV a day later (Figure 2a).…”

“…Adoptive transfer of KLRG1 lo CD127 hi cells results in better survival and memory generation compared with their KLRG1 hi CD127 lo 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 KLRG1 hi CD127 lo 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 KLRG1 lo CD127 hi 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 þ T-cell responses in mice whose death programs have been disabled.…”

“…14 Recent work describing effector CD8 þ T-cell heterogeneity prompted us to re-examine the effects of Bim within subsets of effector CD8 þ T cells with more (KLRG1 lo CD127 hi ) or less (KLRG1 hi C-D127 lo ) memory potential. 1 Wild-type (WT) and Bim À / À mice were infected with LCMV and the kinetics of GP33-specific effector CD8 þ T-cell subsets tracked. The absence of Bim significantly increased the overall numbers of GP33-specific T cells, including both KLRG1 hi CD127 lo and KLRG1 lo CD127 hi CD8 þ effector subsets on days 10 and 15 after infection (Figure 1a).…”

Effector CD8 T cells dedifferentiate into long-lived memory cells

“…The pool of effector CD8 T cells consists of two subsets; the majority (95%) are terminal effectors (TE) that are destined to die and the minority (5%) subset of effector cells, termed memory precursors (MP), survive to give rise to the pool of long-lived memory T cells 5 . These two subsets can be distinguished on the basis of their expression of cell surface markers Klrg1 and CD127 10–12 . So, we analyzed the TE and MP effector subsets at day 8 and quite strikingly both subsets were equally methylated at the CD62L promoter region and they also expressed low levels of CD62L message (Fig.1d, Extended data 1f,1g).…”