Heterogeneity, Persistence, and Clonal Relationships of B Cell-helper T Cells in Lupus

Takanori Sasaki – Brigham and Women's Hospital; Yinan Xiao – Brigham and Women's Hospital; Runci Wang – Brigham and Women's Hospital; Kathryne Marks – Brigham and Women's Hospital; Alice Horisberger – Brigham and Women's Hospital; Yidan Gao – Brigham and Women's Hospital; Pui Lee – Boston Children's Hospital; Yujie Qu – Merck & Co; Marc Sze – Merck & Co; Stephen Alves – Merck & Co; Marc Levesque – Merck & Co; Karen Costenbader – Brigham and Women's Hospital; Deepak Rao – Brigham and Women's Hospital

Abstract Text: T follicular helper (Tfh) cells are prototypical B cell helpers that drive high-affinity antibody production by regulating immune responses within germinal centers of secondary lymphoid organs. However, in chronic inflammation and autoimmune diseases, peripherally located T helper (Tph) cells expand. These cells share effector functions with Tfh, such as producing CXCL13 and IL-21, but lack CXCR5 expression and have reduced BCL6 levels. Although scRNA-seq has enhanced our understanding of B cell-helper T cell heterogeneity, the developmental relationship between Tfh and Tph remains unclear. Using TCR profiling, we describe longitudinal sharing of TCRs between Tph and Tfh cells in SLE patients and controls over a year (diagnosis, 6 months, 1 year). We demonstrate substantial TCR clonal overlap between Tph and Tfh cells, confirming a developmental link between these populations. We then performed scRNA-seq and TCR-seq on 3 SLE patients at 18 months post-enrollment to explore cellular heterogeneity and clonal relationships between sorted Tph and Tfh cells. Sorted Tph cells displayed greater phenotypic heterogeneity than Tfh cells, with both populations containing a cluster of TOX+CXCL13+IL21+ cells that shared highly overlapping TCR repertoires. Using a pristane-induced lupus mouse model, we identified transcriptionally distinct B cell-helper T cell clusters in spleen and lung that shared TCR sequences. Ablating Bcl6 in CD4+ T cells arrested Tfh development and disrupted broader B cell helper differentiation, including Tph cells. These findings demonstrate persistent clonal overlap between Tph and Tfh cells in SLE, suggesting a shared, Bcl6-dependent developmental history.