Toll like Receptor 2 engagement on CD4+ T cells promotes TH9 differentiation and function

• Published in: European journal of immunology 2017-09, Vol.47 (9), p.1513-1524
• Main Authors: Karim, Ahmad Faisal, Reba, Scott M., Li, Qing, Boom, W. Henry, Rojas, Roxana E.
• Format: Article
• Language: English
• Subjects: Acyltransferases - immunology; Animals; Antigens, Bacterial - immunology; Bacterial Proteins - immunology; BATF; CD28 antigen; CD4; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell culture; Cell Differentiation; Cells, Cultured; Cytokines - metabolism; Gene expression; Humans; IL9; Interferon-gamma - metabolism; Interleukin 9; Interleukin-9 - genetics; Interleukin-9 - metabolism; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins - metabolism; PU.1; PU.1 protein; Receptors, Antigen, T-Cell - metabolism; Secretion; Signal Transduction; T cell receptors; T cells; T-Lymphocyte Subsets - immunology; TH9 T cells; TLR2 protein; Toll like receptor 2; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 2 - metabolism; Toll-like receptors; Trans-Activators - metabolism; Transcription factors; Transcriptome
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201646846

We have recently demonstrated that mycobacterial ligands engage Toll like receptor 2 (TLR2) on CD4+ T cells and up‐regulate T‐cell receptor (TCR) triggered Th1 responses in vitro and in vivo. To better understand the role of T‐cell expressed TLR2 on CD4+ T‐cell differentiation and function, we conducted a gene expression analysis of murine naïve CD4+ T‐cells stimulated in the presence or absence of TLR2 co‐stimulation. Unexpectedly, naïve CD4+ T‐cells co‐stimulated via TLR2 showed a significant up‐regulation of Il9 mRNA compared to cells co‐stimulated via CD28. Under TH9 differentiation, we observed up‐regulation of TH9 differentiation, evidenced by increases in both percent of IL‐9 secreting cells and IL‐9 in culture supernatants in the presence of TLR2 agonist both in polyclonal and Ag85B cognate peptide specific stimulations. Under non‐polarizing conditions, TLR2 engagement on CD4+ T‐cells had minimal effect on IL‐9 secretion and TH9 differentiation, likely due to a prominent effect of TLR2 signaling on IFN‐γ secretion and TH1 differentiation. We also report that, TLR2 signaling in CD4+ T cells increased expression of transcription factors BATF and PU.1, known to positively regulate TH9 differentiation. These results reveal a novel role of T‐cell expressed TLR2 in enhancing the differentiation and function of TH9 T cells. TLR2 co‐stimulation promotes TH9 differentiation under polarized condition, whereas significantly upregulates IFN‐γ production in non‐polarized condition. Thus, the impact of TLR2 engagement on CD4+ T cell differentiation may greatly depend on the cytokine environment in which T cells first encounter TLR2 ligands.