Local antigen and inflammation in the lung induce the preferential establishment and maintenance of CXCR6 and CD49a-expressing antigen-specific CD8 TRM cells in the lung parenchyma and airways (MUC1P.900)

Abstract

Acting as sentinels capable of quickly organizing a secondary immune response upon pathogen challenge, resident memory CD8 T (TRM) populations are initially primed by microenvironment cues and APC licensing following acute infection of peripheral tissues. Despite their capacity for heterologous protection against influenza virus (flu) challenge, scant knowledge exists as to factors necessary to establish and maintain airway and lung parenchymal (LP) CD8 TRM cells. In contrast to mechanisms described for other tissues, lung CD8 TRM cell establishment required cognate antigen recognition once cells were recruited to the lung by local inflammation. Furthermore, this combination of local antigen and inflammation formed long-lasting TRM populations in the LP and airways that highly express the chemokine receptor CXCR6 and adhesion molecule CD49a. During a primary intranasal (IN) flu infection, CXCR6 is preferentially expressed on virus-specific CD8 T cells in the airways and LP by day 7 post-infection. Selectively, LP CD8 TRM cells highly express CXCR6, while systemically circulating flu-specific cells achieve only an intermediate expression level. Finally, use of mixed bone marrow chimeras show that wild-type virus-specific memory CD8 T cells predominate over CXCR6-/- cells in the airway and LP after IN infection with Sendai or flu virus. Thus, our data show that local antigen and inflammation coupled with CXCR6 expression is key to establish CD8 TRM cells in the LP and airways.

Dynamics of pulmonary mucosal cytotoxic CD8 T-cells in people living with HIV under suppressive antiretroviral therapy

“…While CXCR6 is expressed under normal homeostatic conditions in lung CD8 T-cells, it is upregulated substantially during inflammatory responses in context of acute lung infections, chronic lung disease, and aging [ 62 – 65 ]. In context of smoking, increased migration and retention of CD8 T-cells armed with effector proteins like GzmB could be one of the contributors towards increased risk of COPD development in smokers and its subsequent tissue-destructive clinical presentation.…”