Characterization of the c-kit-expressing Th17 cells

• Grant number: 16/05013-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): June 01, 2016
• Effective date (End): April 30, 2017
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Fernando de Queiroz Cunha
• Grantee: Kalil Alves de Lima
• Supervisor: Francisco Javier Quintana
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: Harvard University, Boston, United States
• Associated to the scholarship: 13/04942-0 - Molecular mechanisms involved in the enhancement of Th17 response by aryl hydrocarbon receptor (AHR) - correlation with rheumatoid arthritis, BP.DR

Abstract

TH17 subset of helper T cells are characterized by the production of interleukin 17 (IL-17), IL-17F, and IL-22 and have emerged as a subset of effector CD4+ T cells that participates in the development of autoimmune diseases. The aryl hydrocarbon receptor (AHR) is highly expressed on TH17 cells and has an important role in the in vivo and in vitro generation of these cells. Under TH17-cell-inducing conditions AHR activation by 6-formylindolo[3,2-b]carbazole (FICZ), strongly enhances IL-17A production and the proportion of IL-22 producer cells. Curiously, AHR has been described as a nonpathogenic TH17 marker and, under certain conditions its activation is related with regulatory T cell generation. Thus, it remains unclear whether there is a requirement of AHR activation for TH17 cell pathogenicity and what are the downstream targets and biological consequences of AHR activation. In this context, AHR-controlled candidate genes directly involved in maintaining the type 3 innate lymphoid cells (ILC3s) pool have been recently identified, such as the tyrosine kinase receptor c-kit. However it remains unclear if TH17 cells share these mechanisms and what is the role and functional characteristics of c-kit-expressing TH17 cells. Another issue that remains to be addressed is the importance of c-kit signaling for TH17 cells homeostasis. We found that Kit is modulated during in vitro TH17 cells differentiation and we identified the generation of a CD4+IL-17A+c-kit+ subpopulation both in vitro and in vivo. Additionally, we demonstrated that AHR activation increases the frequency of c-kit-expressing TH17 cells and the staining intensity of cells expressing c-kit. Moreover, AHR-deficient naive CD4+ T cells showed significant impairment in their differentiation into c-kit-expressing TH17 cells. Finally, c-kit inhibition increased IL-22 expression, suggesting that c-kit signaling is an IL-22 negative regulator. Taken together, our initial data demonstrate that AHR controls IL-22 production in TH17 cells in a c-kit dependent manner. Thus, the main aim of this project is to investigate the molecular characteristics of c-kit-expressing TH17 cells and the biological relevance of this subpopulation. This project will reveal whether Kit is a marker of nonpathogenic TH17 cells and a possible therapeutic target to multiple sclerosis and other autoimmune diseases. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE LIMA, KALIL ALVES; DONATE, PAULA BARBIM; TALBOT, JHIMMY; DAVOLI-FERREIRA, MARCELA; PERES, RAPHAEL SANCHES; CUNHA, THIAGO MATTAR; ALVES-FILHO, JOSE CARLOS; CUNHA, FERNANDO QUEIROZ. TGF beta 1 signaling sustains aryl hydrocarbon receptor (AHR) expression and restrains the pathogenic potential of T(H)17 cells by an AHR-independent mechanism. CELL DEATH & DISEASE, v. 9, NOV 13 2018. (13/08216-2, 16/05013-1, 13/04942-0)