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_R ) differentiation, polyclonal responses were compared against NP_366-374 /D^b and PA_224-233 /D^b , 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_R 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_224-233 /D^b T cells consistent with T resident memory (T_RM ) status. In contrast, NP_366-374 /D^b T cells exhibit enrichment of effector signatures, upregulating pro-inflammatory mediators even among T_RM . While NP_366-374 /D^b T cells manifest transcripts linked to canonical exhaustion pathways, PA_224-233 /D^b T cells exploit P2rx7 purinoreceptor attenuation. The NP_366-374 /D^b CD103⁺ subset expresses the antimicrobial lactotransferrin whereas PA_224-233 /D^b 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_R and antigen presenting cells in a tissue milieu strongly impact CD8 T cell biology.