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).
Highlights
Rheumatoid Arthritis (RA) is a chronic inflammatory disease targeting peripheral joints leading to bone erosion, impairment of mobility, and decreased quality of life
The source of granzyme A was not identified in this study but we have shown that CD4+ T cells producing granzyme A are present in synovial joints of RA patients [166]
During the last 10 years, new therapeutic trials as well as extended genome wide association studies (GWAS) have provided new data to reinvestigate the contribution of T-cell subsets in RA
Summary
Rheumatoid Arthritis (RA) is a chronic inflammatory disease targeting peripheral joints leading to bone erosion, impairment of mobility, and decreased quality of life. In RA, IL-17-producing T cells might contribute during early stages of the disease or be more prominent in a subtype of RA patients Another level of complexity arises from evidence that Th17 cells are implicated in different immune responses depending on co-expressed cytokines [76]. Th17 cells are present in the gut of patients with Crohn’s disease [87] but IL-17 blockade with Secukinumab was not effective and adverse cases of fungal infections and worsening of the disease were observed [88] In this case, IL-10-producing Th17 cells having a regulatory function [89, 90] might have been targeted contributing to the exacerbation of the disease. IL-6 and ICOS triggering regulate their differentiation [98] (Figure 1)
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