CD6 is expressed on human airway and blood innate lymphoid cells (ILCs) and is upregulated by epithelial alarmins IL-33 and TSLP

Abstract

Rationale: Innate lymphoid cells (ILCs) are recently discovered counterparts of T helper subsets. ILC2s produce type 2 cytokines in response to epithelial alarmins IL-33 and TSLP, contribute to asthma features in animal models, and are elevated in human asthma. CD6 is a co-stimulatory receptor that contributes to pathogenic T cell responses in allergic and autoimmune inflammation. The role of CD6 on ILC subsets is unknown.

Methods: Flow cytometry for CD6 expression on ILC subsets was performed on human blood, lung, and nasal polyps. ILC subsets (CD45+lineage- lymphocytes) were identified as follows: ILC1s as CD127+CD117-CRTH2-; ILC2s as CD127+CRTH2+; and ILC3s as CD127+CD117+CRTH2-. RNA-seq was performed with sorted CD6+ and CD6- blood ILC subsets. Human blood cells were cultured with IL-33, TSLP, or both and ILC2 CD6 expression levels assessed. Mice were challenged with IL-33, and levels of lung ILC2 CD6 were determined.

Results: CD6 was expressed on subpopulations of all human airway ILC subsets (nasal polyps and lung), including lung tissue from a donor with fatal asthma. Bimodal CD6 expression was detected on human blood ILCs, and RNA-Seq revealed unique transcriptomes of CD6+ and CD6-ILCs. Blood ILC2s stimulated with IL33 and/or TSLP revealed increased CD6 expression compared with unstimulated controls. Mouse lung ILC2 CD6 expression was induced by IL-33.

Conclusions: CD6 is expressed on human airway ILCs and is induced on ILC2s by epithelial cytokines critical to asthma. Given the role of CD6 in driving pathogenic T cell responses, strategies targeting CD6 may be relevant to modulating both ILC- and T cell-driven responses in asthma.