TCR-pMHC encounter differentially regulates transcriptomes of tissue-resident CD8 T cells.

To investigate the role of TCR-pMHC interaction in regulating lung CD8 tissue-resident T cell (T ) differentiation, polyclonal responses were compared against NP /D and PA /D , two immunodominant epitopes that arise during influenza A infection in mice. Memory niches distinct from iBALTs develop within the lamina propria, supporting CD103 and CD103 CD8 T generation and intraepithelial translocation. Gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis (WGCNA) identify dominant TCR, adherens junction, RIG-I-like and NOD-like pattern recognition receptor as well as TGF-β signaling pathways and memory signatures among PA /D T cells consistent with T resident memory (T ) status. In contrast, NP /D T cells exhibit enrichment of effector signatures, upregulating pro-inflammatory mediators even among T . While NP /D T cells manifest transcripts linked to canonical exhaustion pathways, PA /D T cells exploit P2rx7 purinoreceptor attenuation. The NP /D CD103 subset expresses the antimicrobial lactotransferrin whereas PA /D CD103 utilizes pore-forming mpeg-1, with <22% of genes correspondingly upregulated in CD103 (or CD103 ) subsets of both specificities. Thus, TCR-pMHC interactions among T and antigen presenting cells in a tissue milieu strongly impact CD8 T cell biology.