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 (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. Previously we reported that circulating T_PH cells are increased in SLE and their activated status was associated with the disease activity. Here we assessed whether T_PH cells contribute to autoantibody production by B cells in SLE.

Methods: Peripheral blood mononuclear cells collected from SLE patients and healthy individuals were analyzed for T and B cell subsets by flow cytometry. T_PH cells were identified as CD3⁺CD4⁺CD45RA^–CXCR5^– cells with a high expression of PD-1. The production of IL-21 by T_PH cells stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin was assessed by intracellular cytokine staining and flow cytometry. To assess functional roles of T_PH cells in B cell maturation and antibody production, T cell populations (T_PH, T_FH, and CXCR5^–PD-1^–memory CD4⁺T cells)and switched memory B (CD19⁺CD27⁺IgD^–) cells were sorted from PBMC using magnetic bead selection and a FACS Aria sorter. Sorted T cell populations and autologous B cells were co-cultured and stimulated with lipopolysaccharide (LPS) and staphylococcus enterotoxin B (SEB) for 7 days. Plasmablast differentiation was assessed by flow cytometry. Antibody levels in culture supernatants were measured by ELISA.

Results: Activated T_PH cells were positively correlated with SLEDAI and anti-DNA antibody titers, and were negatively correlated with serum complement levels and lymphocyte counts.  The frequency of activated T_PH cells was 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, as much as T_FH cells. T_PH cells from lupus patients induced B cell differentiation into plasmablasts and promoted antibody production in T-B cell co-cultures.

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, and T_PH cells provide B cell help. CD4⁺ICOS⁺PD-1⁺cells and plasma cells were reported to be present in the nephritic kidneys and associated with active disease in SLE. These data indicate the contribution of T_PH cells to autoantibody production in aberrant lymphoid organs and the involvement of extra-follicular T-B cell interactions in the pathogenesis of SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/expanded-circulating-peripheral-helper-t-cells-are-associated-with-b-cell-differentiation-in-systemic-lupus-erythematosus/