PD-1^hiCXCR5^– T peripheral helper cells promote B cell responses in lupus via MAF and IL-21

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell–B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here, we evaluated the phenotypes of CD4+ T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1hiCXCR5–CD4+ T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1hiCXCR5–CD4+ T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5– T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not T follicular helper (Tfh) cells, correlated with both clinical disease activity and the frequency of CD11c+ B cells in SLE patients. PD-1hiCD4+ T cells were found within lupus nephritis kidneys and correlated with B cell numbers in the kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells as a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.

Authors

Alexandra V. Bocharnikov, Joshua Keegan, Vanessa S. Wacleche, Ye Cao, Chamith Y. Fonseka, Guoxing Wang, Eric S. Muise, Kelvin X. Zhang, Arnon Arazi, Gregory Keras, Zhihan J. Li, Yujie Qu, Michael F. Gurish, Accelerating Medicines Partnership (AMP) RA/SLE Network, Michelle Petri, Jill P. Buyon, Chaim Putterman, David Wofsy, Judith A. James, Joel M. Guthridge, Betty Diamond, Jennifer H. Anolik, Matthew F. Mackey, Stephen E. Alves, Peter A. Nigrovic, Karen H. Costenbader, Michael B. Brenner, James A. Lederer, Deepak A. Rao