Exploring the role of unconventional T cells in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by sustained synovial inflammation and the gradual destruction of joint structures. Although conventional T cells have historically been viewed as central to RA pathogenesis, increasing attention has recently focused on unconventional T cell subsets, such as natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, and gamma delta T (γδ T) cells. Functioning as a bridge between innate and adaptive immunity, these cells contribute to RA immunopathogenesis by producing cytokines, exerting cytotoxic effects, and interacting with various immune and stromal cells. This review offers a comprehensive analysis of the immunological characteristics and pathogenic roles of unconventional T cell subsets in RA. NKT, MAIT, and γδ T cells contribute to the amplification of inflammatory responses and joint tissue destruction through diverse mechanisms, exhibiting unique tissue tropism and functional plasticity. Recently, novel therapeutic strategies have been developed to target these subsets, including modulation of antigen presentation pathways, inhibition of pro-inflammatory signaling cascades, and reprogramming of cellular functionalities. Advancements in single-cell omics and spatial immune profiling have facilitated the precise identification and characterization of pathogenic unconventional T cell subsets in the RA synovium, thereby paving the way for personalized immunotherapeutic approaches.

Keywords: gamma delta T (γδ T) cells; mucosal-associated invariant T (MAIT) cells; natural killer T (NKT) cells; rheumatoid arthritis (RA); unconventional T cells.

Figure 1

Immunoregulatory and pro-inflammatory roles of NKT cells in RA. This figure illustrates the pathogenic mechanisms of NKT cells in the synovial microenvironment of RA. NKT cells secrete cytokines such as IL-4, IL-12, and IFN-γ, thereby polarizing CD4⁺ T cells into distinct subsets, including Th1, Th2, Th17, and Treg cells. They also interact with FLS, enhancing their proliferation and the production of IL-6 and IL-8, which subsequently stimulate osteoclast precursors and promote the expression of bone-resorptive genes such as TRAP, CTR, and Cathepsin K. Together, these effects underscore the dual role of NKT cells in RA pathogenesis—as regulators of adaptive immunity and as direct contributors to synovial inflammation and joint destruction.

Figure 2

Immunopathogenic role of MAIT cells in RA. This figure illustrates the pathogenic role of MAIT cells in joint inflammation and bone destruction in RA. Upon activation, MAIT cells secrete pro-inflammatory cytokines such as TNF-α and IL-17, which promote the proliferation of FLS, thereby enhancing immune cell recruitment and infiltration. MAIT cells also mediate osteoblast lysis and bone resorption through the release of granzyme B and perforin, and the upregulation of the activating receptor NKG2D. Meanwhile, MAIT cells can interact with B cells to induce autoantibody production, contributing to systemic autoimmunity. Collectively, these mechanisms highlight the multifaceted pathogenic roles of MAIT cells in both local and systemic immune dysregulation in RA.

Figure 3

Pathogenic roles of γδ T cells in RA. This figure illustrates the multifaceted contributions of γδ T cells to synovial inflammation and bone destruction in RA. Distinct subsets of γδ T cells play divergent roles: Vδ1⁺ T cells engage in antigen presentation via CD1d and EPCR, while Vγ9Vδ2⁺ T cells promote IL-17 production, which induces RANKL expression in FLS and osteoblasts, thereby facilitating osteoclast differentiation and bone resorption. Vδ2⁺ T cells also upregulate chemokine receptors CCR5 and CXCR3 through the TNF-α/NF-κB pathway, enhancing their recruitment into inflamed joints. Upon CD3/CD28 co-stimulation, γδ T cells secrete IFN-γ, which can counteract bone resorption, highlighting their context-dependent regulatory potential. Additionally, γδ T cells influence neutrophil function; their depletion enhances neutrophil-derived IL-27 production, which negatively regulates RA severity. These mechanisms underscore the dual inflammatory and regulatory roles of γδ T cells in RA pathogenesis.