Immunomodulatory role of T helper cells in rheumatoid arthritis : a comprehensive research review

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that involves T and B cells and their reciprocal immune interactions with proinflammatory cytokines. T cells, an essential part of the immune system, play an important role in RA. T helper 1 (Th1) cells induce interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and interleukin (IL)-2, which are proinflammatory cytokines, leading to cartilage destruction and bone erosion. Th2 cells primarily secrete IL-4, IL-5, and IL-13, which exert anti-inflammatory and anti-osteoclastogenic effects in inflammatory arthritis models. IL-22 secreted by Th17 cells promotes the proliferation of synovial fibroblasts through induction of the chemokine C-C chemokine ligand 2 (CCL2). T follicular helper (Tfh) cells produce IL-21, which is key for B cell stimulation by the C-X-C chemokine receptor 5 (CXCR5) and coexpression with programmed cell death-1 (PD-1) and/or inducible T cell costimulator (ICOS). PD-1 inhibits T cell proliferation and cytokine production. In addition, there are many immunomodulatory agents that promote or inhibit the immunomodulatory role of T helper cells in RA to alleviate disease progression. These findings help to elucidate the aetiology and treatment of RA and point us toward the next steps. Cite this article: Bone Joint Res 2022;11(7):426-438.

Keywords: Immunomodulatory; Interleukin; Rheumatoid arthritis; T helper cells; aetiology; autoimmune diseases; cartilage destruction; chemokines; cytokines; fibroblasts; inflammatory arthritis; tumour necrosis factor.

Fig. 1

The immune cells involved in the regulation of rheumatoid arthritis (RA). The development of RA involves the interaction of genotype and environmental triggers. Both environmental and genetic factors cause alterations in gene expression, thereby causing the development of RA. Effector T cells, together with B cells and other innate effector cells, form a complex network that promotes the production of pro-inflammatory cytokines, which trigger the activation of resident fibroblast-like synovial cells and lead to cartilage and bone damage. Neutrophils and mast cells, along with macrophages, play an important role in the development of synovitis.

Fig. 2

The differentiation of the naïve CD4⁺ T cell. Naïve CD4 T cells differentiate into distinct T helper subpopulations upon activation, producing spectrum-specific cytokines. Depending on their cytokine profile, different types of Th cells exist. Th1 major cytokine products are interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and interleukin (IL)-2. Th2 cells produce IL-5, IL-9, IL-10, IL-13, IL-25, and dual-regulatory proteins. Another type of immunosuppressive T cells that can express CD25 are called regulatory T cells (Tregs); in addition to CD25, Treg cells also express cytotoxic T-lymphocyte antigen 4 (CTLA-4) and glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR). A third major CD4 Th effector cell population, Th17, was subsequently identified to produce IL-17, and the signature cytokines of Th17 cells include IL-17A, IL-17F, and IL-22. Th17 cell differentiation is promoted by IL-1β, IL-6, IL-21, IL-23, and transforming growth factor-β (TGF-β). Another prominent subpopulation of Th cells are the T follicular helper (Tfh) cells, which promote humoral immunity within the germinal centre (GC). Th9 cells are derived from primary T cells and contain TGF-β and IL-4. TH9 cells produce not only IL-9, but also other cytokines such as IL-10, IL-17, IL-21, and IL-22. The differentiation of Th22 is mainly mediated by the transcription factor aromatic hydrocarbon receptor (AHR). Th22 cells can secrete IL-22, IL-13, IL-26, and TNF-α.

Fig. 3

Involvement of T helper 1 (Th1) cells in the immune regulation of rheumatoid arthritis (RA). Th1 cells secrete cytokines such as interleukin (IL)-2, interferon-γ (IFN-γ), and tumour necrosis factor-α (TNF-α), which participate in immune regulation in the pathogenesis of RA. IL-2 activates signal transducer and activator of transcription 5 (STAT5) to promote the secretion of IFN-γ, and the joint action of IL-2 and IFN-γ causes cartilage destruction and bone erosion. TNF-α can interact with IL-2 and IFN-γ to cause synovitis. In addition, TNF-α can combine with DC11b to inhibit osteoblast differentiation, and it can also combine with tumour necrosis factor receptor 1 (TNFR1) on osteoclast precursor to promote osteoclast formation. These pathological reactions are involved in the pathogenesis of RA.

Fig. 4

Involvement of T helper 2 (Th2) cells in the immune regulation of rheumatoid arthritis (RA). Interleukin (IL)-5 is able to differentiate and mobilize eosinophils from the bone marrow. IL-4 also shows an inhibitory effect on bone resorption by affecting the activity and survival of osteoclasts. Furthermore, IL-4 and IL-13 share the same receptors, and both are capable of activating the signal transduction and activator of transcription 6 (STAT6) signalling pathway. Strong activation of the STAT6 signalling pathway was found in IL-4- and IL-13-induced haematopoietic cells, inducing a shift in macrophage polarization toward an anti-inflammatory ‘M2-like’ phenotype, which is responsible for the suppression of arthritis. In addition, IL-4 and IL-13 have direct anti-inflammatory effects in the synovium of RA, where they reduce the production of IL-1β and tumour necrosis factor (TNF) by synovial macrophages, as well as their expression of CD16 and CD64.

Fig. 5

Involvement of T helper 17 (Th17) cells in the immune regulation of rheumatoid arthritis (RA). Interleukin (IL)-21 induces T cell activation and promotes secretion of pro-inflammatory cytokines in RA. IL-17A has synergistic effects with IL-1 and tumour necrosis factor-α (TNF-α) in upregulating nitric oxide (NO) and prostaglandin E2 (PGE2) production, leading to bone erosion. IL-22 was found to promote osteoclastogenesis, however another study has shown that IL-22 reduces the severity of collagen-induced arthritis by a mechanism associated with elevated IL-10 levels.