Innate and adaptive T cells in asthmatic patients: Relationship to severity and disease mechanisms

Abstract

BackgroundAsthma is a chronic inflammatory disease involving diverse cells and mediators whose interconnectivity and relationships to asthma severity are unclear.ObjectiveWe performed a comprehensive assessment of TH17 cells, regulatory T cells, mucosal-associated invariant T (MAIT) cells, other T-cell subsets, and granulocyte mediators in asthmatic patients.MethodsSixty patients with mild-to-severe asthma and 24 control subjects underwent detailed clinical assessment and provided induced sputum, endobronchial biopsy, bronchoalveolar lavage, and blood samples. Adaptive and invariant T-cell subsets, cytokines, mast cells, and basophil mediators were analyzed.ResultsSignificant heterogeneity of T-cell phenotypes was observed, with levels of IL-13–secreting T cells and type 2 cytokines increased at some, but not all, asthma severities. TH17 cells and γδ-17 cells, proposed drivers of neutrophilic inflammation, were not strongly associated with asthma, even in severe neutrophilic forms. MAIT cell frequencies were strikingly reduced in both blood and lung tissue in relation to corticosteroid therapy and vitamin D levels, especially in patients with severe asthma in whom bronchoalveolar lavage regulatory T-cell numbers were also reduced. Bayesian network analysis identified complex relationships between pathobiologic and clinical parameters. Topological data analysis identified 6 novel clusters that are associated with diverse underlying disease mechanisms, with increased mast cell mediator levels in patients with severe asthma both in its atopic (type 2 cytokine–high) and nonatopic forms.ConclusionThe evidence for a role for TH17 cells in patients with severe asthma is limited. Severe asthma is associated with a striking deficiency of MAIT cells and high mast cell mediator levels. This study provides proof of concept for disease mechanistic networks in asthmatic patients with clusters that could inform the development of new therapies.

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

“…There was no change in blood or sputum MAIT cell frequencies with a 7‐day moderate dose ICS (twice‐daily Qvar 200 μg), but there was a significant 23% decrease in peripheral blood MAIT cell frequencies ( P = 0·03) with just 7 days of systemic corticosteroids (once‐daily prednisolone 20 mg). This effect was specific to MAIT cells; it was not observed with V α 7.2 TCR‐expressing conventional T cells 44, 45…”

“…Of greater significance here is potential confounding by corticosteroid therapy. As will be discussed later, MAIT cell frequencies are very sensitive to therapeutic corticosteroids, which cause a rapid decrease in MAIT cell frequencies 44, 45. Indeed Cho et al 19.…”

“…Whereas iNKT cells are implicated in murine models of allergic airways disease, they are rare in the human airways;62 in comparison, MAIT cells are fivefold to tenfold more abundant in humans than in mice 27. Asthma is characterized by airways inflammation, classically associated with activated allergen‐specific Th2 cells64 secreting IL‐4, IL‐5 and IL‐13, which orchestrate the function of eosinophils, mast cells and B cells 44, 65. There is increasing recognition of disease heterogeneity and some genetic66, 67 and murine68, 69 data implicating IL‐17 in certain phenotypes of asthma.…”

“…We conducted a large‐scale bronchoscopy‐based study of 60 patients spanning the spectrum of asthma severity and phenotypes and 24 healthy controls analysing multiple T‐cell subsets in the context of deep clinical and immunological phenotyping 44. We found no evidence of dysregulation of IL‐17‐secreting CD4 + Th17 cells, but observed a striking deficiency of V α 7.2 + CD161 + T cells in blood, sputum and bronchial biopsy samples44, 45 (Fig. 2).…”

“…Most MAIT cells secrete type 1 cytokines but some clones can produce type 2 cytokines 17, 23, 50. It is possible that in early life during initiating events in the development of allergic and autoimmune disease, such conditions are associated with a skewing towards a type 2 cytokine‐secreting profile in MAIT cells, as occurs with other T‐cell subsets,44, 64 and may occur early in life. Exposure to microbes during early childhood is associated with protection from immune‐mediated diseases 76, 77, 78.…”