Transcriptional characteristics of CD4+ T cells in young asthmatic children: RORC and FOXP3 axis

Background Asthma is a chronic inflammatory disorder, hypothetically caused by autoreactive Th2 cells, whereas Th1 and regulatory T cells may confer protection. The development of Th subpopulations is dependent on the expression of lineage-specific transcription factors. Purpose This study aimed to assess the balance of CD4+ T cell populations in asthmatic children. Methods Peripheral blood mononuclear cells (PBMC) mRNA expression was assessed in 30 asthmatic children (18 patients with mild asthma and 12 with moderate asthma). Real-time polymerase chain reaction (RT-PCR) quantified TBX21, GATA-3, RORC, FOXP3, and EBI3 mRNA expression. Intracellular cytokine expression of IL-2, IL-4, IL-10, and IFN-γ in CD4+ T cells in asthmatic children was measured by flow cytometry. IL-6 and IL-17 cytokines were assessed in serum by enzyme-linked immunosorbent assay (ELISA). Results A significant increase was found in the percentage of CD4+ and CD8+ T cell-producing IL-4, IL-6, and IL-17. A decreased percentage of CD4+ producing IFN-γ in asthmatic children was found. Expression of GATA-3 (Th2), retinoid-related orphan receptor C (RORC) (Th17), and EBI3 were increased in asthmatic patients compared to healthy controls. Expression of FOXP3 (Treg) and TBX21 (Th1) were decreased (P < 0.0001 and P < 0.0001) in asthmatic children. Analysis of transcription factor ratios revealed an increase in the RORC/FOXP3 (P = 0.0001), and a significant decrease of TBX21/GATA-3 (P = 0.0001) ratios in patients with asthma. Conclusion Young asthmatics were characterized by increased IL-4 production and low IFN-γ synthesis. The increased serum IL-17 and IL-6 levels sustained an inflammatory environment in young asthmatics. The results indicate that FOXP3 and RORC mRNA expression could be associated with the sustained inflammatory process, transduced by low immune tolerance by Treg cells. The TBX21/GATA-3 and RORC/FOXP3 ratios dysregulation in asthmatics is consistent with the plasticity existing between Th1, Th17, and Treg cells during inflammation.

[1]  Guancong Deng,et al.  A Common Promoter Variant of TBX21 is Associated with Allele Specific Binding to Yin‐Yang 1 and Reduced Gene Expression , 2011, Scandinavian journal of immunology.

[2]  C. Herrick,et al.  EBI3 deficiency leads to diminished T helper type 1 and increased T helper type 2 mediated airway inflammation , 2011, Immunology.

[3]  S. Koyasu,et al.  Innate Th2-type immune responses and the natural helper cell, a newly identified lymphocyte population , 2011, Current opinion in allergy and clinical immunology.

[4]  A. B. Haghighi,et al.  RORC and Foxp3 axis in cerebrospinal fluid of patients with Neuro-Behçet's Disease , 2011, Journal of Neuroimmunology.

[5]  E. Liu,et al.  The Antiasthma Effect of Neonatal BCG Vaccination Does Not Depend on the Th17/Th1 but IL-17/IFN-γ Balance in a BALB/c Mouse Asthma Model , 2011, Journal of Clinical Immunology.

[6]  B. Ni,et al.  Th9: A New Player in Asthma Pathogenesis? , 2011, The Journal of asthma : official journal of the Association for the Care of Asthma.

[7]  K. Szegedi,et al.  IL-17 and IL-22 in atopic allergic disease. , 2010, Current opinion in immunology.

[8]  Y. Wan,et al.  An Intrinsic Mechanism Predisposes Foxp3-Expressing Regulatory T Cells to Th2 Conversion In Vivo , 2010, The Journal of Immunology.

[9]  Y. Gho,et al.  Distinct Roles of Vascular Endothelial Growth Factor Receptor-1– and Receptor-2–Mediated Signaling in T Cell Priming and Th17 Polarization to Lipopolysaccharide-Containing Allergens in the Lung , 2010, Journal of Immunology.

[10]  J. Bernstein,et al.  A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma , 2010, The Journal of experimental medicine.

[11]  John R. Corboy,et al.  Emerging therapies for treatment of multiple sclerosis , 2010, Journal of inflammation research.

[12]  C. Akdis,et al.  RORC2 Is Involved in T Cell Polarization through Interaction with the FOXP3 Promoter , 2010, The Journal of Immunology.

[13]  W. Paul,et al.  Differentiation of effector CD4 T cell populations (*). , 2010, Annual review of immunology.

[14]  A. Hamzaoui,et al.  Regulatory T cells in induced sputum of asthmatic children: association with inflammatory cytokines , 2010, Multidisciplinary respiratory medicine.

[15]  A. Ray,et al.  Regulatory T Cells in Many Flavors Control Asthma , 2010, Mucosal Immunology.

[16]  William W. Busse,et al.  Asthma: Clinical expression and molecular mechanisms , 2010, Journal of Allergy and Clinical Immunology.

[17]  Y. Belkaid,et al.  Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. , 2009, Immunity.

[18]  Rakesh K. Kumar,et al.  Epigenetic changes in childhood asthma , 2009, Disease Models & Mechanisms.

[19]  C. Bachert,et al.  Decreased FOXP3 protein expression in patients with asthma , 2009, Allergy.

[20]  D. Littman,et al.  Plasticity of CD4+ T cell lineage differentiation. , 2009, Immunity.

[21]  Danila Valmori,et al.  Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor RORγt , 2009, Proceedings of the National Academy of Sciences.

[22]  Daniel J. Campbell,et al.  T-bet controls regulatory T cell homeostasis and function during type-1 inflammation , 2009, Nature Immunology.

[23]  S. Way,et al.  Interleukin‐17 in host defence against bacterial, mycobacterial and fungal pathogens , 2009, Immunology.

[24]  J. Bousquet,et al.  Asthma management pocket reference 2008 * , 2008, Allergy.

[25]  J. Goverman,et al.  Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells , 2008, Nature Medicine.

[26]  P. Barnes.  New molecular targets for the treatment of neutrophilic diseases. , 2007, The Journal of allergy and clinical immunology.

[27]  A. Rudensky,et al.  Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3 , 2007, Nature Immunology.

[28]  H. Hammad,et al.  Recent progress in the biology of airway dendritic cells and implications for understanding the regulation of asthmatic inflammation. , 2006, The Journal of allergy and clinical immunology.

[29]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[30]  A. Hamzaoui,et al.  Cytokine profile in Behçet's disease patients , 2002, Scandinavian journal of rheumatology.

[31]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[32]  W. Ouyang,et al.  Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. , 1998, Immunity.

[33]  Richard A Flavell,et al.  The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells , 1997, Cell.

[34]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[35]  C. Figdor,et al.  Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10. , 1993, Journal of immunology.

[36]  R. Coffman,et al.  Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. , 1986, Journal of immunology.

[37]  M. Goldman,et al.  Interleukin-10 , 2012, BioDrugs.

[38]  D. Littman,et al.  The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. , 2006, Cell.

[39]  D. Berg,et al.  Interleukin 10: an overview. , 1992, Progress in growth factor research.