CXCR3 gene deletion in murine cryptococcal meningoencephalitis leads to a shift in CD4-T Cell transcriptional profile away from hyperactive/cytotoxic phenotype
| Autor: | Jacob William Shelton Martens, Jintao Xu, Kristie D Goughenour, Harini Subbiah, Doyun L. Kwak, Brian L. Parkin, Michal A Olszewski |
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| Rok vydání: | 2021 |
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| Zdroj: | The Journal of Immunology. 206:99.31-99.31 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.206.supp.99.31 |
| Popis: | Cryptococcal meningoencephalitis (CM) is the major cause of infectious neurological death worldwide, mainly affecting immunocompromised patients. CNS damage is often linked to aberrant inflammatory responses following infection. Deletion of CXCR3 in murine CM leads to improved mouse survival and diminished neuroinflammation and damage while maintaining fungal clearance. To establish how CXCR3-deletion suppressed pathological CD4 T cell responses without limiting protective responses, we analyzed transcriptional profiles of brain leukocytes isolated from WT and CXCR3KO with CM using single-cell RNA seq. Distinct clusters of CNS CD4 T-cells were found in CM mice: naïve, effector memory, activated, and exhausted T cells, as well as Th1 and Th2 clusters. The activated T cell clusters (CD69, ICOS, and 4-1BB high) exhibited a Th1-skewed phenotype (T-bet and IFN-γ high). CXCR3KO mice exhibited a marked shift away from these effector T cell clusters, with observed decreases in both memory and activated CD4 T cell phenotypes. In contrast, the naive T cell clusters were maintained in the CXCR3KO mice. The activated CD4 T cell clusters showed significant increase in expression of cytotoxic NKG7 in the WT mice compared to CXCR3KO mice. Interestingly, an IL-17A-expressing γδ-T cell cluster largely absent in the WT was increased in CXCR3KO mice. In conclusion, CXCR3 deletion resulted in a pronounced shift away from highly activated Th1 profile toward a more moderate activated phenotype with a decrease in cytotoxicity, supporting the role of the CXCR3 axis in inducing pathological T cell phenotypes in the brain. The emergence of IL-17A-producing γδ-T cells is unexpected and deserves future studies in the context of protection versus pathology. |
| Databáze: | OpenAIRE |
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