학술논문
PD-1hi CXCR5- T peripheral helper cells promote B cells responses in lupus via MAF and IL-21
Document Type
article
Author
Bocharnikov, Alexandra V; Keegan, Joshua; Wacleche, Vanessa S; Cao, Ye; Fonseka, Chamith Y; Wang, Guoxing; Muise, Eric S; Zhang, Kelvin X; Arazi, Arnon; Keras, Gregory; Li, Zhihan J; Qu, Yujie; Gurish, Michael F; Petri, Michelle; Buyon, Jill P; Putterman, Chaim; Wofsy, David; James, Judith A; Guthridge, Joel M; Diamond, Betty; Anolik, Jennifer H; Mackey, Matthew F; Alves, Stephen E; Nigrovic, Peter A; Costenbader, Karen H; Brenner, Michael B; Lederer, James A; Rao, Deepak A
Source
JCI Insight. 4(20)
Subject
Language
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.