Effector Functions of CD4+ T Cells at the Site of Local Autoimmune Inflammation—Lessons From Rheumatoid Arthritis

Abstract

Infiltration of memory CD4+ T cells in synovial joints of Rheumatoid Arthritis (RA) patients has been reported since decades. Moreover, several genome wide association studies (GWAS) pinpointing a key genetic association between the HLA-DR locus and RA have led to the generally agreed hypothesis that CD4+ T cells are directly implicated in the disease. Still, RA is a heterogeneous disease and much effort has been made to understand its different facets. T cell differentiation is driven by mechanisms including antigen stimulation, co-stimulatory signals and cytokine milieu, all of which are abundant in the rheumatic joint, implying that any T cells migrating into the joint may be further affected locally. In parallel to the characterization and classification of T-cell subsets, the contribution of different effector T cells to RA has been investigated in numerous studies though sometimes with contradictory results. In particular, the frequency of Th1 and Th17 cells has been assessed in the synovial joints with various results that could, at least partly, be explained by the stage of the disease. For regulatory T cells, it is largely accepted that they accumulate in RA synovial fluid and that the equilibrium between regulatory T cells and effector cells is a key factor in controlling inflammation processes involved in RA. Recent phenotypic studies describe the possible implication of a novel subset of peripheral T helper cells (Tph) important for T-B cell cross talk and plasma cell differentiation in the RA joint of ACPA+ (autoantibodies against citrullinated proteins) RA patients. Finally, cytotoxic CD4+ T cells, historically described as increased in the peripheral blood of RA patients have attracted new attention in the last years. In view of the recently identified peripheral T-cell subsets, we will integrate immunological data as well as information on genetic variants and therapeutic strategy outcomes into our current understanding of the width of effector T cells. We will also integrate tissue-resident memory T cell aspects, and discuss similarities and differences with inflammatory conditions in skin (psoriasis) and mucosal organs (Crohn's disease).

New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors

“…These findings may partly account for the autoimmunity against mesenchymal cell-specific antigens and are relevant to IFN-c-abundant conditions in RA synovium which have already been discussed in the previous section. A number of studies have so far indicated IFNc-secreting CD4þ T cells (Th1 subtype), whose differentiation is also promoted by IFN-c, as effector cells in RA [35]. A skewing towards T cells with a Th1 cytokine profile including IFN-c was observed in synovial fluids from RA patients [36].…”

Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

“…Activated T cells migrating to the synovium locally interact with resident macrophages, dendritic cells, synoviocytes, and osteoclasts. Here, several T cell subsets and their complex interactions likely contribute to RA pathology (reviewed in [37]).…”

“…Via their secretion of IL-2, IFN-γ, and TNF-β, Th1 cells potently provide help to other immune cells, resulting in the activation of macrophages and B cells, thereby initiating and perpetuating inflammatory responses in the synovium [37][38][39]. In addition to their helper function in RA inflammation, CD4 + CD28 null cells co-expressing perforin and granzymes, molecules more commonly found in CD8 + cytotoxic T cells, were recently shown to be increased in peripheral blood of a subset of RA patients [40][41][42].…”

“…Moreover, anti-TNF-α treatment was shown to trigger IL-10 production from human Th17 cells [54], suggesting that Th17 cells could also have immunosuppressive capacities in RA. Therefore, it was suggested, that Th17 cells may be important during early stages of the disease, while in later stages Th1 cells differentiated into cytotoxic CD4 + T cells may drive both direct tissue damage and pro-inflammatory cytokine production [37].…”

Effects of Treatment with the Hypomethylating Agent 5-aza-2′-deoxycytidine in Murine Type II Collagen-Induced Arthritis

“…Macrophages can also be subdivided into pro-inflammatory M1 and anti-inflammatory M2 macrophages, that are characterized by the production of the pro-inflammatory cytokines TNF-alpha, IL-6, IL-12, IL-18, and IL-23, and of the anti-inflammatory cytokine IL-10, respectively [9,10]. Both preclinical and clinical evidence coming from rodent models of RA and RA patients indicate that the CD4+T cell belonging to the Th1 and Th17 subsets, along with M1 macrophages, play a key role in the development and maintenance of RA, as opposed to anti-inflammatory Th2 and Th3 cells, and M2 macrophages that seem to play a protective role on the course of the disease [11].…”