Impaired NK activity in the IPF lungs

Abstract

Rationale: One of the features of IPF is the accumulation of senescent cells that produce the senescence-associated secretory phenotype (SASP) that modifies the lung microenvironment. We focus on the alteration of the lung immune response by the SASP, specifically on the natural killer (NK) lymphocytes cytotoxicity against senescence cells. Methods: Fresh lung samples were used for scRNAseq and flow. Blood was collected for the study of plasma cytokines and PBMCs. Results: There was decreased proportion of NK cells in the IPF lung, specifically of the circulatory/cytotoxic NK cells. Such NKs are more senescent, there is a higher proportion of IL6 producing cells and reduced expression of the chemokine receptor CCR2, which is involved in NK recruitment to the lung. scRNAseq analysis of the NK cluster in IPF patients revealed an impaired expression in some of the main NK genes and the fibroblast cluster revealed a profound decrease in the lung capacity to produce chemokines. There is an increase in the proportion of NK cells in the IPF blood with an increase of the circulating/cytotoxic NK population. Additionally, healthy blood NK cells have less migration capacity towards conditioned media (CM) from IPF lung fibroblasts and the culture with the IPF-CM reduces their cytotoxic capacity. Conclusions: Our data reveal that IPF patients have reduced numbers an impaired activity of NK cells in the lung, specifically of the circulating/cytotoxic subpopulation due to a deficiency in the lung capacity of the lung to recruit NKs, which results in their accumulation in the blood. This deficiency in the NK activity and senescence status in the lung could be one of the altered mechanisms perpetrating the accumulation of senescent cells in IPF lungs.