Human lung γδ T cells maintain functionality during inflammatory lung disease.

γδ T cells provide mucosal defense against infection while also contributing to tissue repair. However, data regarding the effect of the human lung environment on γδ T cell functionality remains limited. To address whether lung inflammation impacts γδ T cell functionality, we analyzed lung and matched hilar lymph node (LN) tissue from deceased donors and patients with interstitial lung disease (ILD). We performed high-parameter spectral flow cytometry to examine the expression pattern of phenotypic biomarkers and assess ex vivo function. We identified lung-specific enrichment of γδ T cells with an effector memory phenotype relative to matched regional LN. We then used an ex vivo stimulation approach to interrogate the capacity to protect against infection (granzyme B [GzmB], interferon-γ [IFNγ] and tumor necrosis factor [TNFα]) and promote epithelial cell proliferation (amphiregulin [AREG]). We found that γδ T cells in lung and LN from deceased donors had similar functional properties. While γδ T cell populations from ILD lungs largely maintained cytokine production capacity, expression was diminished relative to LN counterparts. Importantly, lung γδ T cells maintained polyfunctional GzmB, IFNγ and TNFα expression across cohorts. Overall, we report human lung γδ T cells are regionally distinct with conserved functionality in a fibrotic environment.