학술논문

PD-1hi CXCR5- T peripheral helper cells promote B cells responses in lupus via MAF and IL-21
Document Type
article
Source
JCI Insight. 4(20)
Subject
Lupus
Kidney Disease
Autoimmune Disease
Clinical Research
Aetiology
2.1 Biological and endogenous factors
Inflammatory and immune system
Adult
Aged
B-Lymphocytes
CD11c Antigen
CRISPR-Cas Systems
Case-Control Studies
Cell Communication
Cell Culture Techniques
Cell Separation
Cells
Cultured
Coculture Techniques
Female
Flow Cytometry
Gene Knockout Techniques
Humans
Interleukins
Lupus Erythematosus
Systemic
Lymphocyte Activation
Male
Middle Aged
Programmed Cell Death 1 Receptor
Proto-Oncogene Proteins c-maf
RNA-Seq
Receptors
CXCR5
T-Lymphocytes
Helper-Inducer
Accelerating Medicines Partnership (AMP) RA/SLE Network
Adaptive immunity
Autoimmunity
Immunology
T cells
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.