Tumor Necrosis Factor Receptor 2 Signaling Potentiates Proliferation and Suppressive Activities of Follicular Regulatory T Cells

Shotaro kawano¹, Hiroki Mitoma ², Shoichiro Inokuchi ³, Masahiro Ayano ², Yasutaka Kimoto ⁴, Mitsuteru Akahoshi ², Yojiro Arinobu ², Koichi Akashi ², Takahiko Horiuchi ⁵ and Hiroaki Niiro ⁶, ¹Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, ²Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Fukuoka, Japan, Fukuoka, Japan, ³Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Fukuoka, Japan, Fukuoka, Fukuoka, Japan, ⁴Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan, ⁵Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan, Beppu, Japan, ⁶Clinical Education Centre, Kyushu University Hospital, Fukuoka, Japan, Fukuoka, Japan

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: anti-TNF therapy, Basic Science and B cells, T cells, Tumor necrosis factor (TNF)

Session Information

Date: Sunday, November 10, 2019

Title: T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster

Session Type: Poster Session (Sunday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Tumor Necrosis Factor (TNF) α is a multifunctional cytokine with pro-inflammatory and anti-inflammatory characteristics. Regulatory T cells (Treg) express a remarkably high level of TNF Receptor 2 (TNFR2). TNFα modulates the proliferation and function of Treg via TNFR2. Recently, a subset of CD4+ Treg termed follicular regulatory T (Tfr) cells has been found in the lymphoid organs and blood of animals and humans. Function of human Tfr in vivo is not well understood, however it has been shown that Tfr cells limit the function of Tfh cells and repress immunoglobulin secretion from B cells in vitro. Altered number and ratio of Tfr in several autoimmune diseases have been reported, indicating that Tfr might contribute the immunological abnormality in these patients. TNF-R2 signaling enhances suppressive activities in Treg, on the other hand it is still unclear whether Tfr response to TNF-α via TNF-R2. We examine the role of TNF-R2 signaling in this new regulatory cell subset.

Methods: We sorted Tfr(CD3+ CD4+ CXCR5+ CD25+ CD127low or CD14-CD4+ CXCR5+ CD25+ CD127low) and Treg(CD3+ CD4+ CXCR5- CD25+ CD127low or CD14- CD4+ CXCR5- CD25+ CD127low) from mononuclear cells of healthy donor using FACS Aria.
We examined the proliferation and suppressive ability of these cells stimulated with an anti- TNF-R2 agonistic antibody in vitro and performed the transcriptome analysis by RNA-seq.

Results: Foxp3 expression was upregulated in both cell types after stimulation with TNFR2 agonists. TNFR2 agonists greatly enhanced proliferation of Tfr and Treg. Although unstimulated Tfr did not suppress expansion of Tconv (CD14- CD4+ CXCR5- CD25- CD127high) or Tfh(CD14- CD4+ CXCR5+ CD25- CD127high), Tfr stimulated with TNFR2 agonists suppressed expansion of these cells. In coculture with naïve B cells and Tfh cells, TNF-R2-stimulated Tfr suppressed differentiation of naïve B cells into antibody-producing cells and production of immunogloblin from B cells. RNA-seq revealed altered transcriptome of these TNF-R2-stimulated cells in co-stilmulatory/inhibitory molecules and known Treg associated genes (i.e. Foxp3, CTLA-4, LAG3, etc.). Tfr and Treg showed mostly similar gene expression flux, however part of genes was differently regulated.

Conclusion: TNFR2 agonist enhanced proliferation and suppressive function in Tfr in vitro assays. It suggests that Tfr response to TNF-R2-stimulation similarly with Treg, however in part RNA-seq data showed different response after TNF-R2-stimulation between Treg and Tfr. TNF-R2 agonist might be one of the therapeutic strategies in autoimmune diseases.

Disclosure: S. kawano, None; H. Mitoma, None; S. Inokuchi, None; M. Ayano, None; Y. Kimoto, None; M. Akahoshi, None; Y. Arinobu, None; K. Akashi, None; T. Horiuchi, None; H. Niiro, None.

To cite this abstract in AMA style:

kawano S, Mitoma H, Inokuchi S, Ayano M, Kimoto Y, Akahoshi M, Arinobu Y, Akashi K, Horiuchi T, Niiro H. Tumor Necrosis Factor Receptor 2 Signaling Potentiates Proliferation and Suppressive Activities of Follicular Regulatory T Cells [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/tumor-necrosis-factor-receptor-2-signaling-potentiates-proliferation-and-suppressive-activities-of-follicular-regulatory-t-cells/. Accessed .

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/tumor-necrosis-factor-receptor-2-signaling-potentiates-proliferation-and-suppressive-activities-of-follicular-regulatory-t-cells/