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Follicular CXCR5-expressing CD8 T cells curtail chronic viral infection [RNA-seq]

ABSTRACT: In mice chronically infected with lymphocytic choriomeningitis virus (LCMV), we defined a subset of exhausted CD8+ T cells abundantly expressing chemokine receptor CXCR5. These CXCR5+ CD8+ T cells were preferentially localized in B cell follicles, expressing less inhibitory receptors while exhibiting more potent cytolytic activity compared to the CXCR5- subset. Furthermore, we identified Id2-E2A axis as the regulator for the generation of this subset. In line with mouse LCMV chronic infection, we also identified a CXCR5+ CD8+ T cell subset in human HIV patients, which negatively correlated with viral load. Moreover, when adoptively transferred to chronically infected recipients, CXCR5+ subset showed greater therapeutic potential than CXCR5- subset.

ORGANISM(S): Mus musculus

PROVIDER: GSE74148 | GEO | 2016/09/09

SECONDARY ACCESSION(S): PRJNA299178

REPOSITORIES: GEO

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Project description:CD8+ T-cells inhibit virus replication in SIV-infected rhesus macaques (RM). However, it is not clear how SIV infection is controlled in germinal center during chronic SIV infection and limited information exists on the characteristics of CXCR5+ CD8 T cells during chronic SIV/HIV infection. In this study, we used functional genomics to investigate characteristic features and potential mechanisms of CXCR5+ and CXCR5- SIV specific CD8 T cells for the control of pathogenic SIV infection. Six chronically SIV infected RMs, three SIVE660 infected and three SIV mac251 infected that are positive for Mamu A01 allele were selected and SIV-specific CXCR5+ and CXCR5- CD8 T cells were sorted based on CXCR5 expression. RNA from sorted cells were extracted and microarray were performed and analysed. Principal component analysis demonstrated that overall gene expression difference between CXCR5+ and CXCR5- SIV-specific CD8 T cells. Interestingly, the CXCR5+ CD8 T cells revealed a distinct gene signature pattern when compared to CXCR5- CD8 T cells. Unlike the CXCR5- CD8 T cells, the CXCR5+ CD8 T cells expressed higher levels of genes associated with Tfh CD4 T cells such as the master transcription factor Bcl6, CD200, and CTLA4 as well as markers associated with Th2 CD4 T cells such as IL-4R (CD124), CCR4, STAT6, NFATC, and IL-10. Effector molecules typically observed in cytotoxic CD8 T cells such as granzyme A, B, and K were expressed at lower levels on CXCR5+ CD8 T cells compared to their CXCR5- counterparts. CXCR5+ CD8 T cells also expressed higher levels of molecules associated with co-stimulation/antigen presentation such as CD40, CD83, 41BBL and MAMU-DRA. The CXCR5+ CD8 also expressed higher levels of inhibitory receptors such as CD200 and SPRY2 but lower levels of other inhibitory receptors CD160 and CD244. The functional consequence of the expression of these molecules is yet to be determined. Additionally, CXCR5+ CD8 T cells expressed higher levels of the anti-apoptotic gene Bcl-2 and lower levels of the pro-apoptotic gene annexin, suggestive of their better survival potential during chronic SIV infection. Collectively, these results demonstrate that SIV specific CXCR5+ CD8 T cells possess a unique gene expression signature compared to SIV-specific CXCR5- CD8 T cells.

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Follicular CXCR5-expressing CD8 T cells curtail chronic viral infection [RNA-seq]

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