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

Abstract

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.

Memory T Cell Dynamics in the Lung during Influenza Virus Infection

“…Lung Trm, similar to Trm characterized in other tissues, are a self-sustaining population that are maintained with minimal need for replenishment by the circulating memory T cell pool (19,20,(95)(96)(97). In the lung, CD4 + and CD8 + Trm congregate either within or around inducible bronchial-associated lymphoid tissue, respectively, and are also enriched in areas where the lung tissue has been remodeled postinfectionassociated injury (19,98,99). Trm express a variety of adhesion molecules and proteins that facilitate their longterm retention and survival in the lung (19) (Fig.…”

“…Studies in animal models have defined key developmental requirements of lung Trm and identified factors within the lung microenvironment that promote Trm differentiation and maintenance. Optimal development of influenza virus-specific CD8 + Trm in the lung requires the following: 1) local cognate Ag recognition in the tissue (15,20,110), 2) exposure to locally produced TGF-b (99,102,103), and 3) the presence of IFN-g-secreting CD4 + T cells (111) (Fig. 1).…”

“…1). Because Trm development in the lung is driven by local cognate Ag recognition, changes in epitope availability over the course of a virus infection impacts the selection of different specificities of T cells into the Trm pool (15,19,99). As such, the immunodominance hierarchy within the influenza-specific lung Trm compartment does not reflect that of the circulating memory T cell pool.…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…67,72,73 Further, TCR signal can induce the expression of anti-viral protein IFITM3 (Interferon Induced Transmembrane Protein 3) in lung T RM cells. IFITM3 protects lung T RM cells from direct viral infection-induced cell death.…”

“…These lung T RM niches are the tissue repair-associated regions and co-localize with the production of T RM promoting factors TGF-β and IL-15. 47,72 Notably, the regeneration of damaged airway epithelium is also TGF-β-dependent, 78 providing an example of complex functions of TGF-β signaling in both local immunity and tissue homeostasis. The gradual decline of lung T RM cells is caused by the completion of injured lung regeneration and the shrinking of lung T RM niches.…”