Increased TIGIT⁺PD‑1⁺CXCR5^‑CD4⁺T cells are associated with disease activity in rheumatoid arthritis

It is well established that increased programmed cell death protein 1 (PD-1)⁺C-X-C chemokine receptor type 5 (CXCR5)^- CD4⁺T cells are found in patients with rheumatoid arthritis (RA). T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a co-inhibitory receptor that is expressed on T cells. However, the expression patterns and immunomodulatory roles of TIGIT on PD1⁺CXCR5^-CD4⁺T cells in RA are poorly understood. Patients with RA were recruited and their clinical characteristics were recorded. The expression level of TIGIT on PD-1⁺CXCR5^-CD4⁺T cells was examined using flow cytometry. Subsequently, the correlation between various parameters of TIGIT⁺PD-1⁺CXCR5^-CD4⁺T cells [percentage of the cells, mean fluorescence intensity (MFI) of PD-1 and TIGIT in the cells] in patients with RA and clinical data, including autoantibodies, inflammatory indicators and RA activity, were analyzed. In addition, the risk factors of RA were assessed using univariate and multivariate regression analyses. The percentages of TIGIT⁺CXCR5^-CD4⁺T, PD-1⁺CXCR5^-CD4⁺T, TIGIT⁺PD-1⁺CXCR5^-CD4⁺T, TIGIT^-PD-1⁺CXCR5^-CD4⁺T cells, the MFI of PD-1 in these cells and the MFI of TIGIT in TIGIT⁺PD-1⁺CXCR5^-CD4⁺T cells were revealed to be significantly increased in patients with RA compared with those in healthy individuals. The parameters of TIGIT⁺PD-1⁺CXCR5^-CD4⁺T cells (percentage and/or MFI of PD-1) in patients with RA were found to be associated with the levels of anti-cyclic citrullinated peptide antibodies, rheumatoid factor and inflammatory markers, such as lymphocyte count, lymphocyte percentage, neutrophil percentage, lymphocyte-to-monocyte ratio, neutrophil-to-lymphocyte ratio, systemic immune inflammation index, derived neutrophil-to-lymphocyte ratio, erythrocyte sedimentation rate and C-reactive protein. In addition, the MFI of PD-1 in TIGIT⁺PD-1⁺CXCR5^-CD4⁺T cells was associated with a disease activity score of 28 and the patient visual analogue scale. Multivariate logistic regression analysis demonstrated that the percentage of TIGIT⁺PD-1⁺CXCR5^-CD4⁺T cells and the MFI of PD-1 in TIGIT⁺PD-1⁺CXCR5^-CD4⁺T cells were risk factors for RA. The present study suggests that the increase in TIGIT⁺PD-1⁺CXCR5^-CD4⁺T cells is associated with the production of autoantibodies and RA activity and may serve a role in RA pathogenesis.