Cell-contact-dependent activation of CD4⁺ T cells by adhesion molecules on synovial fibroblasts

Abstract

Objective: To determine how cell–cell contact with synovial fibroblasts (SF) influence on the proliferation and cytokine production of CD4⁺T cells.

Methods: Naïve CD4⁺T cells were cultured with SF from rheumatoid arthritis patients, stimulated by anti-CD3/28 antibody, and CD4⁺T cell proliferation and IFN-γ/IL-17 production were analyzed. To study the role of adhesion molecules, cell contact was blocked by transwell plate or anti-intracellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1(VCAM-1) antibody. To study the direct role of adhesion molecules for CD4⁺T cells, CD161⁺or CD161^- naïve CD4⁺T cells were stimulated on plastic plates coated by recombinant ICAM-1 or VCAM-1, and the source of IFN-γ/IL-17 were analyzed.

Results: SF enhanced naïve CD4⁺T cell proliferation and IFN-γ/IL-17 production in cell-contact and in part ICAM-1-/VCAM-1-dependent manner. Plate-coated ICAM-1 and VCAM-1 enhanced naïve CD4⁺T cell proliferation and IFN-γ production, while VCAM-1 efficiently promoting IL-17 production. CD161⁺naïve T cells upregulating LFA-1 and VLA-4 were the major source of IFN-γ/IL-17 upon interaction with ICAM-1/VCAM-1.

Conclusion: CD4⁺T cells rapidly expand and secrete IFN-γ/IL-17 upon cell-contact with SF via adhesion molecules. Interfering with ICAM-1-/VCAM-1 may be beneficial for inhibiting RA synovitis.

Key words:

• CD4⁺ T cells
• CD161
• IFN-γ
• IL-17
• Intracellular adhesion molecule-1
• Rheumatoid arthritis
• Synovial fibroblasts
• Vascular cell adhesion molecule-1

Acknowledgments

We thank S. Nakagawa for technical assistance.

Conflict of interest

MH, T. Fujii, MF, HI, and T. Mimori are affiliated with a department that is supported financially by five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., AbbVie GK., Eisai Co., Ltd.). MH and MF have received grant and research support from Astellas Pharma Inc. and Pfizer Japan Inc. JH works for Astellas Pharma Inc. HI has received grant and research support from Astellas Pharma Inc., Pfizer Japan Inc., NTT communications, and Takeda Pharmaceutical Co., Ltd. T. Fujii has received grant and research support from Takeda Pharmaceutical Co., Santen Pharmaceutical Co., Ltd., Astellas Pharma Inc., Asahi Kasei Pharma Corporation, and Daiichi Sankyo Co., Ltd. T. Mimori has received grant and research support from Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd., and speakers bureau from AbbVie GK., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd. The sponsors were not involved in the study design; in the collection, analysis, interpretation of data; in the writing of this manuscript; or in the decision to submit the article for publication. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science in Japan (MH) http://kaken.nii.ac.jp/d/p/23791113.ja.html and in part by Astellas Pharma Inc. (Special Coordination Funds for Promoting Science and Technology). Astellas Pharma Inc. had no role in the collection, analysis or the decision to submit the manuscript for publication. Publication of this article was approved by an intellectual property committee composed of representatives from Kyoto University and Astellas Pharma Inc.

Supplementary material available online