Heterogeneity of B cell helper T cells in murine pristane-induced lupus

Abstract

T follicular helper (Tfh) cells are considered the major T cells capable of stimulating B cells responses, and these cells can promote germinal center responses and autoantibody production in autoimmune diseases. However, additional T cell population distinct from Tfh cells can also provide B cell help in autoimmune diseases, including a subset of effector PD-1hi CXCR5-CD4+ T cells, termed peripheral helper T (Tph) cells, enriched in the synovial tissues of rheumatoid arthritis patients. Tph cells highly expressed B cell helper molecules such as IL21 and upregulated chemokine receptors CCR2 and CCR5. Single-cell sequencing results revealed different transcriptomic features of Tph cells, including an elevated ratio of BLIMP-1/BCL6, and distinguished them from Tfh cells. Identification of Tph cells highlighted the heterogeneity within the B cell helper CD4+ T cells in autoimmune diseases. However, the development of B cell helper CD4+ T cells and their role in disease progression remain obscure. Therefore, we characterized B cell helper CD4+ T cells by single-cell/TCR sequencing in pristane-induced lupus murine models. By reclustering the B cell helper CD4+ T cells, we further identified Tfh (Bcl6+Cxcr5+ CD4+ T cells) and T cells that appeared distinct from Tfh cells but with expression of IL21 and CD200, representing potential Tph cells. Shared TCR sequences between Tfh and Tph cells indicated a clonal link between B cell helper CD4+ T cells. Significant reduction of B cell helper CD4+ T cells, including Tph cells, in the Bcl6fl/flCD4cre mice, suggested Bcl6, the lineage TF of Tfh cells, was required for their development. The decrease of B cell helper cells further led to the loss of tertiary lymphoid structures (TLS) in the lung tissues. Overall, the results indicated that pristane-induced lupus murine models might be an appropriate tool to study the heterogenous B cell helper CD4+ T subsets. Those B cell helper T cells were crucial for lupus disease development in murine models and could be important therapeutic targets.