BAFF regulates follicular helper t cells and affects their accumulation and interferon-γ production in autoimmunity.
OBJECTIVE
Follicular helper T (Tfh) cells are critical for the development of protective antibodies 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 aim of this study was to determine the contribution of BAFF to Tfh cell responses in autoimmunity.


METHODS
We analyzed the properties of Tfh cells in lupus-prone mice sufficient or deficient in BCMA. Adoptive transfer studies and mixed bone marrow chimeras were used to test BCMA signaling in T cells. We assessed BAFF stimulation of Tfh cells through in vitro cell cocultures and in vivo depletion studies using flow cytometry.


RESULTS
In Nba2 mice, Tfh cells expressed the BAFF receptors BCMA and B lymphocyte stimulator receptor 3 (BR-3) and accumulated in the spleen when BCMA was absent. BCMA deficiency in T cells promoted the expansion of Tfh cells, GC formation, autoantibody production, and interferon-γ (IFNγ) production by Tfh cells through BR-3. IFNγ-producing Tfh cells increased BAFF expression in dendritic cells. Blocking BAFF or IFNγ in vivo reduced Tfh cell accumulation and reduced autoimmunity in BCMA-deficient animals. Moreover, circulating Tfh-like cells that expressed BR-3 (but not BCMA) were elevated in patients with systemic lupus erythematosus, and this correlated with serum BAFF and IFNγ levels.


CONCLUSIONS
In Nba2 mice, BCMA negatively regulates Tfh cell expansion, while BAFF signaling through BR-3 promotes Tfh cell accumulation. Our findings suggest that the balance between BCMA and BR-3 signaling in Tfh cells serves as a checkpoint of immune tolerance.
University of Virginia, Charlottesville.
Christine M
CM
Coquery
William M
WM
Loo
Nekeithia S
NS
Wade
Annelise G
AG
Bederman
Kenneth S
KS
Tung
Janet E
JE
Lewis
Henry
H
Hess
Loren D
LD
Erickson
D000328:Adult; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000502:physiology*; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D053301:B-Cell Maturation Antigen / Q000378:metabolism; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D013729:Terpenes / Q000494:pharmacology
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; C505719:TNFSF13B protein, human; D013729:Terpenes; C490176:Tnfrsf17 protein, mouse; C505720:Tnfsf13b protein, mouse; C009042:pristane; D007371:Interferon-gamma