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Is there a role for type 2 CD8+ T cells in patients with steroid-resistant asthma?

2019; Elsevier BV; Volume: 144; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2019.07.022

1097-6825

Erwin W. Gelfand, Timothy S.C. Hinks,

Immune Cell Function and Interaction

Different types of inflammation and effector cells contribute to asthma pathogenesis, with genetics and varied environmental triggers dictating the effector pathways.1Gelfand E.W. Joetham A. Wang M. Takeda K. Schedel M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation.Immunol Rev. 2017; 278: 63-86Crossref Scopus (19) Google Scholar As a consequence, patients can differ from each other, as well at different stages of their disease. Predominant effector molecules in asthmatic airway inflammation include the type 2 cytokines IL-4, IL-5, and IL-13. IL-17 and airway neutrophilia might play a role in response to certain triggers. For several decades, type 2 cytokine release has been associated with CD4+ TH2 cells and corticosteroid responsiveness. Other cell types are now shown to be sources of these cytokines, including mast cells and other T-cell subsets, including type 2 innate lymphoid cells and TH9 cells, activated in response to the epithelial cytokines IL-25 and IL-33 and thymic stromal lymphopoietin. Despite use of inhaled and often oral corticosteroids, many asthmatic patients exhibit persistent symptoms, type 2 inflammation, airway eosinophilia, and airway obstruction. Different molecular signatures of the airway inflammatory cells have been demonstrated as a means to classify asthma but, for the most part, have not assigned these signatures to specific cellular subsets. In experimental models of asthma, predominantly in mice, contributing subsets have been defined and characterized.1Gelfand E.W. Joetham A. Wang M. Takeda K. Schedel M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation.Immunol Rev. 2017; 278: 63-86Crossref Scopus (19) Google Scholar In addition to type 2–secreting CD4+ TH2 cells and type 2 innate lymphoid cells, CD8+ T cells have been shown to be capable of releasing significant amounts of IL-5 and IL-13. IFN-γ–producing CD8+ TC1 cells exposed to IL-4 undergo transdifferentiation to IL-5– and IL-13–producing type 2 CD8+ (TC2) cells responsible for the full array of lung allergic responses (Fig 1).1Gelfand E.W. Joetham A. Wang M. Takeda K. Schedel M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation.Immunol Rev. 2017; 278: 63-86Crossref Scopus (19) Google Scholar IL-4 was required for Gata3 expression in these cells and IL-4–dependent recruitment of GATA3 to the IL-13 promoter. Of note, these CD8+ TC2 cells were corticosteroid insensitive compared with CD4+ TH2 cells.1Gelfand E.W. Joetham A. Wang M. Takeda K. Schedel M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation.Immunol Rev. 2017; 278: 63-86Crossref Scopus (19) Google Scholar Terminal transcriptional differentiation to IL-13 production was regulated by activation of the steroidogenic enzyme cytochrome P450 family 11 subfamily A member 1 (CYP11A1).1Gelfand E.W. Joetham A. Wang M. Takeda K. Schedel M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation.Immunol Rev. 2017; 278: 63-86Crossref Scopus (19) Google Scholar Pulmonary TC2 cell recruitment was facilitated by upregulation of the leukotriene B4 receptor BLT1.1Gelfand E.W. Joetham A. Wang M. Takeda K. Schedel M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation.Immunol Rev. 2017; 278: 63-86Crossref Scopus (19) Google Scholar A unique feature of these converted CD8+ TC2 cells was their sensitivity to hypoxia.2Ning F. Takeda K. Schedel M. Domenico J. Joetham A. Gelfand E.W. Hypoxia enhances CD8(+) TC2 cell-dependent airway hyperresponsiveness and inflammation through hypoxia-inducible factor 1α.J Allergy Clin Immunol. 2019; 143: 2026-2037Abstract Full Text Full Text PDF Scopus (12) Google Scholar Through activation of hypoxia-inducible factor 1α, exposure to a hypoxic environment resulted in expansion of these cells, increasing IL-13–secreting cells capable of enhancing the full array of allergen-driven responses. The extent to which murine studies can be extrapolated to human asthma is controversial. Studies focusing on the role of CD8+ T cells in asthmatic patients are infrequent. Nonetheless, a role for CD8+ T cells has been suggested in asthmatic patients with an overlap of the features described in mouse CD8+ effector TC2 cells. Activated human CD8+ T cells are similarly more resistant to corticosteroids than CD4+ T cells.1Gelfand E.W. Joetham A. Wang M. Takeda K. Schedel M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation.Immunol Rev. 2017; 278: 63-86Crossref Scopus (19) Google Scholar Therapeutic corticosteroids in asthmatic patients result in significant decreases in numbers of CD4+ (but not CD8+) T cells in peripheral blood.3Corrigan C.J. Haczku A. Gemou-Engesaeth V. Doi S. Kikuchi Y. Takatsu K. et al.CD4 T-lymphocyte activation in asthma is accompanied by increased serum concentrations of interleukin-5. Effect of glucocorticoid therapy.Am Rev Respir Dis. 1993; 147: 540-547Crossref PubMed Scopus (260) Google Scholar Expression of CYP11A1 in CD8+ T cells is sensitive to vitamin D3, and an epistatic effect between genetic variants in CYP11A1 and the vitamin D receptor was protective against the development of childhood asthma.4Schedel M. Jia Y. Michel S. Takeda K. Domenico J. Joetham A. et al.1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter.Nat Commun. 2016; 7: 10213Crossref Scopus (47) Google Scholar A role for CD8+ T cells has been suggested in patients with fatal asthma, smoking asthmatic patients, and patients with virus-induced asthma.1Gelfand E.W. Joetham A. Wang M. Takeda K. Schedel M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation.Immunol Rev. 2017; 278: 63-86Crossref Scopus (19) Google Scholar Where directly examined, numbers were similar or even greater than numbers of CD4+ T cells in the airways. Similar to mouse CD8+ TC2 cells, human TC2 cells express the prostaglandin D2 receptor chemoattractant receptor–homologous molecule expressed on TH2 cells (CRTH2), the cysteinyl leukotriene receptor 1, and BLT1.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar When activated, these elicit TC2 cell chemotaxis and production of chemokines and type 2 and other cytokines, resulting in eosinophil recruitment and survival.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar Numerous clinical studies observed associations between airway CD8+ T-cell frequencies and asthma, with increased numbers in bronchoalveolar lavage (BAL) fluid over CD4+ T cells and correlations with airway hyperresponsiveness.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar Increased numbers of CD8+ T cells in BAL fluid were associated with eosinophilic asthma.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar In bronchial biopsy specimens of asthmatic patients, CD8+ T cells were enriched in the lamina propria despite regular inhaled corticosteroid use.6van Rensen E.L. Sont J.K. Evertse C.E. Willems L.N. Mauad T. Hiemstra P.S. et al.Bronchial CD8 cell infiltrate and lung function decline in asthma.Am J Respir Crit Care Med. 2005; 172: 837-841Crossref PubMed Scopus (122) Google Scholar In the large Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes (U-BIOPRED) study, increased numbers of CD3+ and CD8+ (but not CD4+) T cells characterized asthmatic patients with the highest submucosal eosinophilia, high fraction of exhaled nitric oxide values, frequent exacerbations, and high oral corticosteroid use.7Kuo C.S. Pavlidis S. Loza M. Baribaud F. Rowe A. Pandis I. et al.A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED.Am J Respir Crit Care Med. 2017; 195: 443-455Crossref PubMed Scopus (126) Google Scholar In a 7.5-year prospective follow-up of adults with atopic asthma,6van Rensen E.L. Sont J.K. Evertse C.E. Willems L.N. Mauad T. Hiemstra P.S. et al.Bronchial CD8 cell infiltrate and lung function decline in asthma.Am J Respir Crit Care Med. 2005; 172: 837-841Crossref PubMed Scopus (122) Google Scholar decreases in postbronchodilator FEV1 correlated not with bronchial biopsy eosinophil counts or airway remodeling but with bronchial biopsy CD8+ (and not CD4+) T-cell counts. These findings were confirmed at a 14-year follow-up.8den Otter I. Willems L.N. van Schadewijk A. van Wijngaarden S. Janssen K. de Jeu R.C. et al.Lung function decline in asthma patients with elevated bronchial CD8, CD4 and CD3 cells.Eur Respir J. 2016; 48: 393-402Crossref PubMed Scopus (32) Google Scholar Beyond these associations, what is known about type 2 cytokine–secreting human CD8+ T cells specifically? Several studies reported increased peripheral blood TC2 cell frequencies in asthmatic patients, an association stronger than with TH2 cells.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar BAL fluid CD8+ T-cell lines produced more IL-5 in asthmatic patients than in healthy control subjects.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar Numbers of both CD8+ and CD4+ IL-4–producing T cells were increased in BAL fluid in patients with asthma and eosinophilic bronchitis, but the strength of this association was stronger for TC2 than TH2 cells.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar Resting blood CD8+ T cells produced more IL-4 in asthmatic patients than in healthy subjects.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar Peripheral blood CD8+IL-4+ cell counts were increased in patients with allergic asthma, and CD8+IL-5+ cell counts were significantly increased in patients with eosinophilic asthma; this was not true for CD4+IL-5+ cells.9Stoeckle C. Simon H.U. CD8(+) T cells producing IL-3 and IL-5 in non-IgE-mediated eosinophilic diseases.Allergy. 2013; 68: 1622-1625Crossref Scopus (22) Google Scholar A subset of CD8+IL-6 receptor α+ effector memory T cells expressing the type 2–associated nuclear transcription factor GATA-3 produced high levels of IL-5 and IL-13, and their numbers were increased in peripheral blood in asthmatic patients.10Lee N. You S. Shin M.S. Lee W.W. Kang K.S. Kim S.H. et al.IL-6 receptor alpha defines effector memory CD8+ T cells producing Th2 cytokines and expanding in asthma.Am J Respir Crit Care Med. 2014; 190: 1383-1394Crossref PubMed Scopus (31) Google Scholar Similarly, peripheral blood CD8+IL-13+ TC2 cell counts were increased in asthmatic patients and correlated with severity and an eosinophilic phenotype, whereas increases in CD4+IL-13+ TH2 cell counts were observed only in patients with mild disease and not in those with eosinophilic disease.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar TC2 frequencies were associated with nasal polyposis and smoking. Moreover, frequencies of peripheral blood CD8+IL-13+ TC2 cells were positively correlated with type 2 lung inflammation, measured based on sputum T-cell IL-4 expression, despite no association with blood CD4+IL-13+ TH2 cells.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar In a separate cohort, using CRTH2 as a surface marker for type 2 cells, CD4+CRTH2+ TH2 cells were not associated with eosinophilic disease; in contrast, peripheral blood CD8+CRTH2+ T cells were strongly associated with a severe eosinophilic phenotype.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar The findings of stronger disease associations for TC2 than TH2 cells emerge from several studies where specifically examined. Although CD4+IL-13+ TH2 cells were enriched in bronchial biopsy specimens but only in patients with mild, steroid-naive atopic asthma, in the same study increases in CD8+IL-13+ TC2 cell counts were detected in bronchial biopsy specimens and BAL fluid in patients with eosinophilic asthma.5Hilvering B. Hinks T.S.C. Stoger L. Marchi E. Salimi M. Shrimanker R. et al.Synergistic activation of pro-inflammatory type-2 CD8(+) T lymphocytes by lipid mediators in severe eosinophilic asthma.Mucosal Immunol. 2018; 11: 1408-1419Crossref PubMed Scopus (38) Google Scholar The combination of molecular reprogramming, corticosteroid insensitivity, and expansion under hypoxia position CD8+ TC2 cells as important contributors to asthma pathophysiology, especially in those with corticosteroid-resistant asthma. Increased frequencies and activation of CD8+ TC2 cells in blood and airway tissues and the associations with eosinophilic phenotypes despite use of corticosteroids that are often stronger than those observed with TH2 cells support this notion. Although bulk transcriptomic tissue studies have revealed convergence of asthma disease pathology on common pathways, the cell type–specific molecular pathology is often undefined. Future studies involving large patient cohorts followed longitudinally, whole-exome sequencing, and improved single-cell technologies (eg, single nucleus RNA sequencing) will allow for more precise identification of asthma-driven molecular changes, their association with specific cell types and deleterious genetic variants, and correlations with clinical severity. Only in this way will we be able to more directly implement personalized medicine with the advent of many new biologics.