IL-6 Receptor α Defines Effector Memory CD8+ T Cells Producing Th2 Cytokines and Expanding in Asthma

Rationale: Cytokine receptors can be markers defining different T-cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor alpha (IL-6R alpha) with asthma was reported, suggesting their involvement in asthma. Objectives: To determine whether and how IL-6R alpha defines a distinct effector memory (EM) CD8(+) T-cell population in health and disease. Methods: EM CD8(+) T cells expressing IL-6R alpha (IL-6R alpha(high)) were identified in human peripheral blood and analyzed for function, gene, and transcription factor expression. The relationship of these cells with asthma was determined using blood and sputum. Measurements and Main Results: A unique population of IL-6R alpha(hig)h EM CD8 T cells was found in peripheral blood. These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of GATA3 and decreased levels of T-bet and Blimp-1 in comparison with other EM CD8(+) T cells. In fact, GATA3 was required for IL-6R alpha expression. Patients with asthma had an increased frequency of IL-6R alpha(high) EM CD8(+) T cells in peripheral blood compared with healthy control subjects. Also, IL-6R alpha(high) EM CD8(+) T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial sup erantigens. Conclusions: Human IL-6R alpha(high) EM CD8(+) T cells is a unique cell subset that may serve as a reservoir for effector CD8(+) T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.