Of interest to the etiology of demyelinating autoimmune disease is the potential to aberrantly activate CD4+ T cells due to cross-recognition of multiple self-epitopes such as has been suggested for MOG35-55 and NFM15-35. NFM15-35 is immunogenic in C57BL/6 mice but fails to induce demyelinating disease by polyclonal T cells despite having the same TCR contact residues as MOG35-55, a known encephalitogenic antigen. Despite reported cross-reactivity with MOG specific T cells, the polyclonal response to NFM15-35 did not expand threshold numbers of MOG38-49 tetramer positive T cells. Furthermore, NFM lacked functional synergy with MOG to promote EAE because NFM-/- mice developed an identical disease course to wild type mice after challenge with MOG35-55. Single cells analysis of encephalitogenic T cells using the pMHC monomer based 2D micropipette adhesion frequency assay confirmed that NFM was not a critical antigen driving demyelinating disease because NFM18-30 specific T cells in the CNS were predominantly reactive to MOG38-49. The absence of NFM contribution to disease allowed mapping of the amino acids required for encephalitogenicity and expansion of high affinity, MOG specific T cells that defined the polyclonal response. Alterations of N-terminal residues outside of the NFM15-35 core nonamer promoted expansion of high affinity, MOG38-49 tetramer positive T cells and promoted consistent EAE induction, unlike mice challenged with NFM15-35. While NFM15-35 is immunogenic and cross-reactive with MOG at the polyclonal level, it fails to expand a threshold level of encephalitogenic, high affinity MOG specific T cells.
Tissue-resident memory CD8+ T cells (TRM) are strategically located in peripheral tissues, especially at mucosal surfaces, where they can provide protection against invading pathogenic microbes. In the lungs, TRM play a critical role in limiting disease and transmission of respiratory viruses; however, the heterogeneity present in TRM populations in the human lung remains largely unexplored. Here we show that human lungs harbor transcriptionally, epigenetically, and phenotypically distinct populations of memory CD8+ T cells expressing the tissue residency-associated markers CD69 and CD103. High-dimensional flow cytometry and single-cell RNA sequencing of memory CD8+ T cells isolated from human lungs shows that heterogeneity exists both between and within CD69+ CD103− and CD69+ CD103+ subsets, with transcriptional diversity among the CD69+ CD103− subset being most prominent. Single-cell ATACseq demonstrates that similar levels of epigenetic diversity exist between and within these different TRM subsets. However, flow cytometry and single-cell RNAseq of influenza- and SARS-CoV-2-specific lung TRM demonstrates that heterogeneity between CD69+ CD103− and CD69+ CD103+ subsets is largely eliminated when the cells are specific for a common antigen. Together, these data illuminate underappreciated and unexplored aspects of heterogeneity in TRM populations in humans. Supported by grants from NIH/NIAID (75N93019R00028) and NIH/NHLBI (R35 HL150803)
Previous reports have demonstrated the many effects of IL-27 on CD4 T cell activation and differentiation, in addition to a role for IL-27 in cancer therapies mediated by cytolytic CD8 T cells. However, as IL-27 is produced by many cell types during infection, and the IL-27 receptor (IL-27R) is widely expressed on NK cells, as well as on activated CD4 and CD8 T cells, the direct effects of IL-27 signaling on CD8 T cell function are less well understood. We used a murine model of influenza infection in combination with co-transfer of congenic wild type (WT) and IL-27R−/− OT-I CD8 T cells to investigate whether IL-27 signaling had a direct effect on virus-specific CD8 T cell function in vivo. We observed a dramatic reduction in the frequency and number of IL-27R−/− OT-I compared to their WT OT-I counterparts within the same host following influenza infection, indicating a CD8 T cell-intrinsic role for IL-27 in the generation of an acute anti-viral response. This defect was observed in the spleen, lung interstitium, airways and the lung-draining mediastinal lymph node, indicating a systemic defect in development of the CD8 T cell effector response in the absence of IL-27R signaling. Both memory precursor and short lived effector cells were reduced in the absence of IL-27R signaling indicating potential defects in both effector and memory generation. We are currently exploring the mechanism of defective effector CD8 T cell generation in the absence of cell-intrinsic IL-27R signaling. Overall, these findings show a cell-intrinsic role for IL-27 signaling in the generation of a robust effector CD8 T cell response following influenza infection.
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