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

Abstract

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 a (IL-6Ra) with asthma was reported, suggesting their involvement in asthma.Objectives: To determine whether and how IL-6Ra defines a distinct effector memory (EM) CD81 T-cell population in health and disease. Methods: EM CD81 T cells expressing IL-6Ra (IL-6Ra 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-6Ra high EM CD8 1 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 1 T cells. In fact, GATA3 was required for IL-6Ra expression. Patients with asthma had an increased frequency of IL-6Ra high EM CD81 T cells in peripheral blood compared with healthy control subjects. Also, IL-6Ra high EM CD8 1 T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial superantigens.Conclusions: Human IL-6Ra high EM CD8 1 T cells is a unique cell subset that may serve as a reservoir for effector CD8 1 T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.

Understanding memory CD8 + T cells

“…Indeed, a distinct population of T EM cells expressing high levels of IL-6R α (also known as CD126) was found at a greater frequency in asthma patients. Althoug it was unclear whether their increased presence led to higher disease severity [91], these cells were shown to produce high levels of IL-15, IL-13, IFN- γ and GATA3 compared with T EM cells that express low levels of IL-6R α . Furthermore, this population also expressed higher levels CCR4, which in important in recruiting T cells into the airways of asthma patients [91].…”

Prenatal Stress, Prematurity, and Asthma

“…Both IL-6 and IL-8 are increased after cesarean delivery of full term infants [65], which may be relevant due to modestly increased asthma risk among infants delivered by cesarean section [66]. IL-6 is associated with increased airway resistance [67] and acts on a subset of effector memory CD8+ T-cells to enhance production of Th2 cytokines [68]. IL-8, a pro-inflammatory cytokine influenced by ozone and particulate matter, acts as a potent chemoattractant of neutrophils leading to airway inflammation [69].…”

Viruses and bacteria in Th2‐biased allergic airway disease

“…Thus, IL-33, TSLP, and Notch signaling might be the possible therapeutic target in RSV-induced Th2 responses. In addition to the classical Th2 cells and ST2L + cells, a novel human subset of IL-6Ra high effector memory CD8 + T cells was identified to exclusively release IL-5 and IL-13 after HRSV infection (47). IL-6Ra high effector memory CD8 + T cells were detected in high numbers in the peripheral blood of asthma subjects (47), suggesting a role of the cells in promoting Th2 responses in asthma (Fig.…”

“…Without the effect of the enterotoxin, CRSwNP tissue exposure to S. aureus alone led to IL-5 expression via TLSP and IL-33 productions (data not published). Even though IL-6Ra high effector memory CD8 + T cells are involved in virus-induced Th2 response, they also trigger IL-5 and IL-13 expressions in response to the bacterial superantigens SEB and TSST-1 (47). In mouse, an adhesion molecule of S. aureus 'iron-regulated surface determinant A' mediated IL-4 secretion from splenocytes (57).…”