A Tale of Two Immune Cells in Rheumatoid Arthritis: The Crosstalk Between Macrophages and T Cells in the Synovium

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Joint inflammation of RA is closely related to infiltration of immune cells, synovium hyperplasia, and superfluous secretion of proinflammatory cytokines, which lead to cartilage degradation and bone erosion. The joint synovium of RA patients contains a variety of immune cellular types, among which monocytes/macrophages and T cells are two essential cellular components. Monocytes/macrophages can recruit and promote the differentiation of T cells into inflammatory phenotypes in RA synovium. Similarly, different subtypes of T cells can recruit monocytes/macrophages and promote osteoblast differentiation and production of inflammatory cytokines. In this review, we will discuss how T cell-monocyte/macrophage interactions promote the development of RA, which will provide new perspectives on RA pathogenesis and the development of targeted therapy.

Keywords: RA; T cells; macrophage; pathogenesis; targeted therapy.

Figure 1

The regulation of T cells by macrophages in RA is mainly reflected on the 1) recruitment: Macrophages-secreted CXCL16 induces migration of CXCR6⁺ T cells in RA joint synovium, which is regulated by TNF-α. 2) Th17 differentiation: abnormal expression of CD200R1 was associated with Th17/Treg imbalance in patients with active RA. Treatment with anti-CD3 mAb, peptidoglycan, or LPS-activated monocytes from peripheral blood can induce IL-17 secretion from CD4⁺ T cells. Treatment with anti-CD3/CD28-activated CD4⁺ T cells can boost Th17 polarization of PBMCs that were treated with RA synovial fluid from healthy donors, which may be due to the up-regulation of IL-6 and IL-1β from monocytes. Human CD14^+/bright CD16⁺ monocytes promoted Th17 differentiation of memory CD4⁺ T cells. Activation of the IL-34-CSF-1R pathway in synovial macrophages can promote Th17 differentiation of T cells. IRF5 promotes monocytes/macrophages-induced Th17 differentiation of T cells. 3) induction of hyper-activation of T cells by monocytes/macrophages: IL-15 lead to increased expression of MHCII and reduced expression of the SOCS3 in macrophages, which activate the proliferation of autoreactive CD4⁺ T cells in RA. Monocytes rescue synovial T cells from glucocorticoid-induced apoptosis. LPS + IFNγ-treated M-CSF-dependent macrophages inhibit the proliferation, activation and cytokine production of CD4⁺ T cells.

Figure 2

The regulation of macrophages by T cells in RA mainly includes effects on macrophage 1) recruitment: Synovial Th17 cells secrete CCL20 and CCL2, which has chemotactic effects on monocytes. The induction of monocyte death requires activation of CD4⁺ CD25^- responder T cell–cell contact in a FAS-L/FAS dependent manner. 2) cytokine production: anti-CD3 activated peripheral CD4⁺ T cells can activate monocytes to produce IL-1 in a CD40-CD40L dependent manner. TCR/CD3-mediated T cell activation induces monocyte TNF-α production, which is induced by IL-15. IL-10 production in RA synovial-membrane mononuclear cells and M-CSF-primed macrophages is activated by interaction with cytokine-stimulated T cells in a PI3K- and p70S6K-dependent manner. and 3) osteoclast differentiation: Th1, Th17 and Th22 can induce osteoclast differentiation via producing IL-15, RANKL, M-CSF and IFN-γ. However, IFNγ also disrupts the differentiation of osteoclasts via degrading RANK bridging protein TRAF6, this suggests that IFNγ⁺ T cells can promote or hinder osteoclastogenesis under different conditions.

Figure 3

Mutual interaction between macrophages and T cells includes ICAM3/DC-SIGN, CD40/CD80 and CCL21/CCR7-Th17. The interaction of macrophages/T cells via DC-SIGN/ICAM-3 promotes the additional activation of synovial macrophages and production of EMMPRIN and MMP-1. IL-7 promotes co-stimulatory molecules CD80 and CD40 on CD14+ monocytes in the presence of CD4+ T cells. In the early stages of RA, CCL21-induced M1 cytokines favor the differentiation of naïve T cells into Th17 cells. In the erosive stages of RA, CCL21 aggravates RA osteoclastogenesis via M1 macrophages-mediated Th17 differentiation.