Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus

Abstract

Pathologic T cell-B cell interactions drive disease in systemic lupus erythematosus (SLE). The T cells that activate B cell responses include T peripheral helper (Tph) and T follicular helper (Tfh) cells, yet the developmental and clonal relationships between these B cell-helper T cell populations are unclear. Here we use T cell receptor (TCR) profiling to demonstrate substantial clonal overlap between Tph and Tfh cells in the circulation of patients with SLE. Expanded Tph and Tfh cell clones persist over the course of 1 year in patients with a new diagnosis of SLE, and clones are observed to shift both from Tfh to Tph cells and from Tph to Tfh cells over time. High resolution analysis of cells sorted as Tph cells (CXCR5- PD-1hi) from SLE patients revealed considerable heterogeneity among these cells and highlighted a subpopulation of cells with transcriptomic features of activated B cell-helper T cells. This cell population, marked by expression of TOX and CXCL13, was found in both sorted Tph and Tfh cells, and was clonally linked in these two populations. Analysis of B cell-helper T cells in murine pristane-induced lupus demonstrated similar populations of Tph and Tfh cells in both lung and spleen with strong clonal overlap. T cell-specific loss of Bcl6 prevented accumulation of Tfh cells and reduced accumulation of Tph cells in pristane-treated mice, indicating a role for Bcl6 in the survival and expansion of both populations. Together, these observations demonstrate a shared developmental path among pathologically expanded Tph and Tfh cells in SLE. The persistence of expanded Tph and Tfh cells clones over time may explain the lack of stable tolerance induction by immunosuppressive medications or by B cell depletion.