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BAFF Regulates T Follicular Helper Cells in Autoimmunity

Coquery, Christine
Format
Thesis/Dissertation; Online
Author
Coquery, Christine
Advisor
Erickson, Loren
Abstract
T follicular helper (TFH) cells are critical for the development of protective antibodies (Ab) via germinal center (GC) B-cell responses; however, uncontrolled TFH cell expansion activates autoreactive B-cells to produce antibodies that cause autoimmunity. The mechanisms that control TFH cell homeostasis remain largely unknown. The work described here shows that the receptor B Cell Maturation Antigen (BCMA) has a critical role in CD4+ T cells for regulating TFH cell responses in autoimmune lupus. Under lupus-prone or inflammatory conditions, TFH cells express BCMA and the BAFF receptor BR3. In BCMA-deficient animals, TFH cells accumulate in the spleen. Mixed bone marrow chimeras and adoptive transfer studies demonstrated that BCMA deficiency in T cells was sufficient to promote the abnormal expansion of TFH cells, leading to germinal center formation and autoantibody production. The accumulation of BCMA deficient TFH cells was mediated by BAFF signals transduced through BR3. We identified increased frequencies of both splenic-dendritic cells (DCs) and neutrophils, both potent BAFF producers, which co-localized in the T cell zone. DCs and neutrophils induced IFNγ production by TFH cells that in turn increased BAFF expression in DCs. Blocking BAFF or IFNγ in vivo, as well as neutrophil depletion, reduced TFH cell accumulation and improved autoimmunity in BCMA deficient animals. Moreover, we observed elevated circulating CD4+ T cells and TFH-like cells that express BR3 (but not BCMA) in SLE patients, which correlated with serum BAFF and IFNγ titers. These findings identify a new BCMA-BAFF axis that controls TFH cell homeostasis and suggests the balance between BCMA and BR3 signaling in TFH cells serves as a checkpoint of immune tolerance.
Language
English
Published
University of Virginia, Department of Microbiology, Immunology, and Cancer Biology, PHD, 2014
Published Date
2014-09-08
Degree
PHD
Rights
All rights reserved (no additional license for public reuse)
Collection
Libra ETD Repository

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