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

ABSTRACT: Tissue-resident memory T cells (Trm) play a central role in regional immunity within non lymphoid tissues to efficiently protect against reinfection as well as to control persistent pathogen infection. Although single-cell transcriptomics analysis of Trm in various diseases have uncovered a phenotypic and functional heterogeneity of Trm, the underlying molecular mechanisms directing such diversity are poorly defined. To better understand these mechanisms, we used the model of infection with the parasite Toxoplasma gondii (T. gondii), which establishes a persistent infection in the central nervous system (CNS) controlled by brain CD8+ Trm. Through single-cell transcriptomic analysis of brain CD8+ T cells from T.gondii-infected mice, we uncovered that brain Trm subsets have an heterogenous expression of the transcriptional regulator Id2, and that these differences in Id2 levels correlated with different functional states. Using mixed bone marrow chimeras, our results revealed that T-cell specific Id2-deficiency caused parasite-specific Trm to develop an aberrant phenotype in a cell-intrinsic manner, characterized by diminished effector functions and reduced expression of the tissue retention molecules CD49a and CXCR6. This phenotype was similarly observed upon overexpression of E2A, a transcription factor negatively regulated by Id2, in parasite-specific CD8+ T cells. Conversely, the loss of Id2 in brain-infiltrating CD8+ T cells led to the accumulation of exhausted PD1+ Tox+ CD8+ Trm cells, whereas Id2 overexpression repressed the acquisition of the exhaustion phenotype and promoted the accumulation of pathogen-specific CD8+ T cells in the brain. Overall, our study indicates that Id2 expression level dictates the acquisition of an effector vs. exhausted phenotype by CD8+ Trm during chronic CNS pathogen infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE270492 | GEO | 2025/05/22

REPOSITORIES: GEO