Background/Purpose: Autoreactive T-B cell interactions in lymphoid tissue have been thought to play a crucial role in the autoantibody production in systemic lupus erythematosus (SLE). These CD4⁺ T cells are known as follicular helper (T_FH) cells expressing CXCR5, a chemokine receptor promoting cell migration to B cell follicles. Recently, a new population of ‘peripheral helper’ T (T_PH) cells that help B cell responses has been discovered in synovium of patients with rheumatoid arthritis. Like T_FH cells, T_PH cells express ICOS and PD-1, but these cells lack CXCR5. Here we assessed whether T_PH cells are involved in the pathogenesis of SLE.

Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from SLE patients and age- and sex-matched healthy individuals as controls. The patients fulfilled the 1997 ACR criteria. A total of 65 patients provided blood samples (57 women and 8 men). The median age of patients was 41 years (range, 21-52), and the median SLEDAI score was 4 (range 0-31). The majority of patients (n=54) were taking medications such as glucocorticoids, hydroxychloroquine, tacrolimus, cyclosporine, azathioprine, mizoribine, and mycophenolate mofetil. Isolated PBMCs were stained with antibodies against CD3, CD4, CD45RA, CXCR5, PD-1, ICOS, CD19, CD20, CD27, CD38, CD180, IgD, and HLA-DR, and were analyzed by flow cytometry. T_PH were defined as PD-1^hiCXCR5^–CD45RA^–CD4⁺CD3⁺ cells. Frequency and activated status of T_PH cells were compared with those of other immune cells including B cell subsets, clinical data (anti-DNA antibody titers, serum complement levels, and lymphocyte counts) and SLEDAI. IL-21-producing capacity of T_PH upon stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin was analyzed with intracellular staining.

Results: The proportions of T_PH cells as well as activated T_PH cells were increased in SLE patients than healthy controls. The frequency of T_PH cells positively correlated with SLEDAI and anti-DNA antibody titers, and negatively correlated with serum complement levels. Activated T_PH cells were also associated with SLEDAI, anti-DNA antibody titers, serum complement levels, and lymphocyte counts. We did not observe differences in relative frequencies of T_PH cells in SLE patients regardless of treatment. As previously reported, the frequency of plasmablasts was increased in SLE patients and correlated with disease activity. The frequency of activated T_PH cells were correlated with that of plasmablasts and activated switched memory B cells. Lupus T_PH cells had the capacity to produce IL-21, a pivotal cytokine for B cell and plasma cell differentiation.

Conclusion: Our data demonstrate that the increased frequency and activated status of T_PH cells are associated with the disease activity as well as enhanced B cell responses in SLE. CD4⁺ICOS⁺PD-1⁺ cells and plasma cells were reported to be present in the nephritic kidneys and associated with active disease in SLE. Because T_PH cells also express ICOS and PD-1, the interaction of T_PH cells with B cells may occur in the lupus kidneys and contribute to the autoantibody production in the peripheral tissue in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/peripheral-helper-t-cells-in-systemic-lupus-erythematosus/