Id2 levels determine the development of effector vs. exhausted tissue-resident memory CD8+T cells during CNS chronic infection

Abstract

ABSTRACTTissue-resident memory T cells (Trm) are essential for regional immunity in non-lymphoid tissues. Although single-cell transcriptomics have revealed Trm heterogeneity in various diseases, the molecular mechanisms behind this diversity are unclear. To investigate this, we usedToxoplasma gondii(T. gondii) infection, which persists in the central nervous system (CNS) and is controlled by brain CD8+Trm. Our single-cell transcriptomic analysis of brain CD8+T cells fromT. gondii-infected mice showed heterogeneous expression of the transcriptional regulator Id2, correlating with different functional states. Using mixed bone marrow chimeras, we found that Id2-deficiency in T cells caused parasite-specific Trm to develop an altered phenotype with diminished effector functions and reduced expression of CD49a. Furthermore, loss of Id2 in brain-infiltrating CD8+T cells led to the accumulation of exhausted PD1+Tox+CD8+Trm cells, while Id2 overexpression repressed T cell exhaustion. Overall, our study shows that Id2 levels dictate the acquisition of effectorvs.exhausted phenotypes in CD8+Trm during chronic CNS infection.One sentence SummaryId2 expression level regulates the functional heterogeneity of brain Trm during CNS chronic infection