Dataset Information

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 (TR ) differentiation, polyclonal responses were compared against NP366-374 /Db and PA224-233 /Db , 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 TR 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-? signaling pathways and memory signatures among PA224-233 /Db T cells consistent with T resident memory (TRM ) status. In contrast, NP366-374 /Db T cells exhibit enrichment of effector signatures, upregulating pro-inflammatory mediators even among TRM . While NP366-374 /Db T cells manifest transcripts linked to canonical exhaustion pathways, PA224-233 /Db T cells exploit P2rx7 purinoreceptor attenuation. The NP366-374 /Db CD103+ subset expresses the antimicrobial lactotransferrin whereas PA224-233 /Db 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 TR and antigen presenting cells in a tissue milieu strongly impact CD8 T cell biology.

SUBMITTER: Yoshizawa A

PROVIDER: S-EPMC6531858 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Yoshizawa Akihiro A Bi Kevin K Keskin Derin B DB Zhang Guanglan G Reinhold Bruce B Reinherz Ellis L EL

European journal of immunology 20170929 1

To investigate the role of TCR-pMHC interaction in regulating lung CD8 tissue-resident T cell (TR ) differentiation, polyclonal responses were compared against NP366-374 /Db and PA224-233 /Db , 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 TR generation and intraepithelial tran ...[more]

PMID: 28872670

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Project description:The discovery of naturally occurring T cell receptors (TCRs) that confer specific, high-affinity recognition of pathogen and cancer-associated antigens remains a major goal in cellular immunotherapies. The contribution of the CD8 co-receptor to the interaction between the TCR and peptide-bound major histocompatibility complex (pMHC) has previously been correlated with the activation and responsiveness of CD8+ T cells. However, these studies have been limited to model systems of genetically engineered hybridoma TCRs or transgenic mouse TCRs against either a single epitope or an array of altered peptide ligands. CD8 contribution in a native human antigen-specific T cell response remains elusive. Here, using Hepatitis C Virus-specific precursor CTLs spanning a large range of TCR affinities, we discovered that the functional responsiveness of any given TCR correlated with the contribution of CD8 to TCR/pMHC binding. Furthermore, we found that CD8 contribution to TCR/pMHC binding in the two-dimensional (2D) system was more accurately reflected by normalized synergy (CD8 cooperation normalized by total TCR/pMHC bonds) rather than synergy (total CD8 cooperation) alone. While synergy showed an increasing trend with TCR affinity, normalized synergy was demonstrated to decrease with the increase of TCR affinity. Critically, normalized synergy was shown to correlate with CTL functionality and peptide sensitivity, corroborating three-dimensional (3D) analysis of CD8 contribution with respect to TCR affinity. In addition, we identified TCRs that were independent of CD8 for TCR/pMHC binding. Our results resolve the current discrepancy between 2D and 3D analysis on CD8 contribution to TCR/pMHC binding, and demonstrate that naturally occurring high-affinity TCRs are more capable of CD8-independent interactions that yield greater functional responsiveness even with CD8 blocking. Taken together, our data suggest that addition of the normalized synergy parameter to our previously established TCR discovery platform using 2D TCR affinity and sequence test would allow for selection of TCRs specific to any given antigen with the desirable attributes of high TCR affinity, CD8 co-receptor independence and functional superiority. Utilizing TCRs with less CD8 contribution could be beneficial for adoptive cell transfer immunotherapies using naturally occurring or genetically engineered T cells against viral or cancer-associated antigens.

Dataset Information

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

Publications

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

Similar Datasets

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