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

Abstract

Tissue-resident memory T cells (Trms) 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 performed single-cell transcriptomic analysis of brain CD8⁺ T cells from mice chronically infected with Toxoplasma gondii. This analysis revealed a heterogeneous expression of the transcriptional regulator Id2 in brain Trms, correlating with different functional states. Using mixed bone marrow chimeras, we found that Id2 deficiency in T cells caused parasite-specific Trms to develop an altered phenotype with diminished effector functions and reduced expression of the key tissue-retention molecules CD49a, CXCR6, and CD103. Furthermore, Id2 loss 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⁺ Trms during chronic CNS infection.

Keywords: CD8 T cells; CNS; CP: Immunology; Id2; T cell exhaustion; Toxoplasma gondii; Trm; chronic infection; transcriptional regulation.