BAtCHing stem-like T cells during exhaustion

Abstract

Long-term pathogen and tumor control as well as checkpoint immunotherapies rely on ‘stem-like’ CD8⁺ T cells. New results uncover BACH2 as a key regulator of this subpopulation and solve an important piece of the puzzle.

Fig. 1 |. BACH2 promotes CD8⁺ T cell differentiation toward T_ex^stem cells while antagonizing T_ex^term cell fates via epigenetic and transcriptional mechanisms in the early stage of chronic viral infection.

BACH2 promotes the upregulation of the prosurvival factor Bcl-2 in T_ex^stem cells and modulates the expression of tissue-homing factors (promoting the upregulation of CD62L and CC R7 and the downregulation of CC R2 and CXCR6), which favor the localization of T_ex^stem cells to the splenic white pulp (grey background cells, left) and away from the red pulp (red background cells, right) and non-lymphoid organs, where T_ex^term cells are enriched. Furthermore, BACH2 suppresses the expression of effector molecules, such as granzyme B (GrzB), and inhibitory receptors, such as PD-1, and attenuates signaling downstream of the TCR (left, blunt arrows). Mechanistically, BACH2 mediates the repression of T_ex^term cell differentiation by restricting chromatin accessibility to the regulatory regions of the TFs RUNX3 and BATF (middle, above) and suppressing the expression of genes encoding BLIMP-1 (Prdm1) and BATF (middle, below).