T Cells in Osteoarthritis: Drivers, Repairers, or Bystanders in Osteoarthritis?

The involvement of the immune system in osteoarthritis (OA) is undisputed but the specific role of lymphoid cells in its pathogenesis has continued to fuel debate. In this issue of Arthritis & Rheumatology, the study by Moradi et al ¹ revisits the role of T cells in OA and persuades us that they contribute to OA pathogenesis. Historically, there is a body of evidence that suggests a possible causal role for T cells in OA. This includes the identification of increased numbers of memory T cells in the OA synovium, some which show early activation markers and evidence of oligoclonality; the presence of ectopic lymphoid tissue in up to 30% of OA synovial biopsy samples; the association of HLA genotypes with OA risk from genetic linkage studies; evidence of specific autoantigens, for example, to type II collagen; and increased levels of T cell cytokines in OA synovial fluid. ² , ³ More recent observations include reports of individuals with OA being nearly eight times more likely to develop inflammatory arthritis after checkpoint inhibitor treatment for cancer than patients without a history of OA. ⁴ Some of the evidence for an association has not stood the test of time; for instance, large‐scale genome‐wide association studies, largely superseding linkage studies, have not confirmed that HLA alleles contribute to OA genetic risk. ⁵

In the study by Moradi et al, they first perform a detailed longitudinal characterization of immune cell profiles in a well‐validated surgical joint destabilization model in mice. The authors demonstrate a cyclical increase in T cells in the synovium starting immediately after surgery that is more evident in the destabilized joint (OA) compared with sham‐operated control and surgery‐naïve groups. These cells have increased ratios of Th1/2‐ and Th17‐associated cytokines, suggesting a proinflammatory rather than pro‐resolving function. The regulation of T cell numbers appears dominant over myeloid cells, and although a cyclical pattern is also demonstrated for monocyte/macrophage numbers (out of phase with the T cells), there is no significant difference in their levels over time comparing OA and sham‐operated joints. Lymphocyte subsets have not been phenotyped in depth, and so it is difficult to determine whether these subsets have arisen from resident memory T cells (eg, CD8⁺CD69⁺CD103⁺), whether they have differentiated in situ to bona fide T helper cell subsets expressing their master transcription factor and associated chemokine receptors, or whether these cells have migrated into the joint as a consequence of the injury perturbation. Indeed, injury or inflammation would induce a leaky synovial joint with infiltration of a wide repertoire of CD4 or CD8 T cells because these cells are intrinsically migratory and have the habit of being retained in the tissue beyond the period of the traumatic or inflammatory “insult.” ⁶

The big question is whether T cells truly contribute to disease outcomes and, if so, whether targeted therapies would benefit patients. Moradi et al demonstrate a correlation between patient‐reported pain and T cell numbers in synovial biopsies of patients with early posttraumatic or established OA. However, because all pathologies within the OA joint correlate weakly with pain and generally correlate with one another, it is difficult to use this as evidence for causality. The authors also show evidence in vitro that T cells are capable of making matrix metalloproteinases, which they suggest could be contributing to degradation of the articular cartilage, a primary feature of OA. Based on single‐cell data from OA synovium, ⁷ other cell types, principally fibroblasts and macrophages, appear to be making a much bigger contribution to this when considering the whole tissue.

Mechanical joint stress is a primary factor in OA pathogenesis, ⁸ and pathologic changes in the joint, as well as inflammatory gene regulation from whole‐joint extracts, are abrogated when the joint is immobilized after surgical joint destabilization in mice, either by prolonged anesthesia or sciatic/femoral neurectomy. ⁹ Both immune cells and stromal cells of the cartilage and synovium are responsible for mechanosensitive regulation of inflammatory genes through a variety of described mechanisms. ¹⁰ Sterile tissue injury responses in other organs also activate a myriad of other classical innate immune processes, including activation of clotting cascades and the complement pathway, that contribute to innate immune cell (neutrophils, monocytes, innate lymphoid cells) recruitment and activation and pave the way for repair. T cells (and B cells) enter the joint later, ensure sterility of the wound, and also contribute to wound resolution and repair in a non–antigen‐dependent manner. ¹¹

A dominant role for the innate immune response in OA is supported by STEpUP OA, a large‐scale proteomic analysis of the synovial fluid in over 1,300 individuals with early‐ and late‐stage radiographic OA. ¹²  Core pathways identified in this analysis that predicted having more severe radiographic disease include “epithelial to mesenchymal transition,” “complement,” and “coagulation.” Targeting of both complement and coagulation pathways are shown to be disease modifying in surgically induced OA in mice. ¹³ , ¹⁴ There are no published reports of joint protection when OA is induced in Rag1^−/− and Rag2^−/− mice, in which T and B cells are absent, or in severe combined immunodeficient mice, although we are aware of unpublished studies from our own laboratory and others in which no OA protection is seen in these strains. Moradi et al failed to see robust protection in mice in which depleting anti‐CD3 antibodies were given either at the time of surgery or once disease was established, although these experiments are somewhat problematic and hard to interpret because the anti‐CD3 clone 145.2C11 is a potent agonistic monoclonal antibody, so any depletion (reported here in the spleen but not synovial tissue) may arise through activation‐induced cell death. Further studies and alternative approaches would help to clarify this.

Rheumatologists are familiar with the classic immune‐mediated diseases of the joint that have strong T cell dependence. As trainees, we are taught to distinguish inflammatory arthritis from OA by examining the cell type and number within the synovial fluid. OA joint fluid is typically paucicellular and mainly monocytic. Diseases such as rheumatoid arthritis (RA) demonstrate compelling evidence for T cell dependence, including highly cellular synovial fluid (often >50% neutrophils); strong genetic associations with HLA alleles and T cell receptor modulator genes; diagnostic and prognostic autoantibodies such as those against citrullinated peptides; and clinical response to immunomodulation, including specific T cell–targeted therapies such as abatacept. The latter acts as an agonist at CTLA‐4 and is efficacious in active RA as well as suppressing development of RA when given to at‐risk but asymptomatic individuals. ¹⁵ Repurposing of disease‐modifying antirheumatic drugs in OA has been generally disappointing, either failing to meet primary study end points when targeting cytokines such as interleukin‐1 (IL‐1), tumor necrosis factor, and IL‐6, or by using general immunosuppressive treatments such as hydroxychloroquine. Modest changes of questionable clinical significance are seen with methotrexate across knee and hand OA. ¹⁶ Intra‐articular glucocorticoid injection is superior to placebo in reducing pain, but it is short lived (<12 weeks), and repeated injections has been shown to accelerate structural disease. ¹⁷

Taken together, the evidence suggests that T cells are unlikely primary drivers of OA and targeting their activity is unlikely to deliver beneficial clinical outcomes. Their presence in the joint is not questioned, and there may be aspects of disease that lymphocytes contribute to, but the relative importance of these to effector or even regulatory pathways in OA may be modest. T cell–dependent autoantibody production is not a feature of OA nor animal models thereof. Very little is understood about “inflammatory flares” in OA, which are often unpredictable but can occur with increased mechanical stress or intercurrent illness. It is tempting to speculate that the adaptive immune cells have a greater contribution to such episodes, but at present these remain poorly characterized.

AUTHOR CONTRIBUTIONS

Both authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Vincent confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.

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