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

Tissue-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 used Toxoplasma 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 from T. 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 effector vs. exhausted phenotypes in CD8 ⁺ Trm during chronic CNS infection.