Fas receptor expression in germinal-center B cells is essential for T and B lymphocyte homeostasis.
Fas is highly expressed in activated and germinal center (GC) B cells but can potentially be inactivated by misguided somatic hypermutation. We employed conditional Fas-deficient mice to investigate the physiological functions of Fas in various B cell subsets. B cell-specific Fas-deficient mice developed fatal lymphoproliferation due to activation of B cells and T cells. Ablation of Fas specifically in GC B cells reproduced the phenotype, indicating that the lymphoproliferation initiates in the GC environment. B cell-specific Fas-deficient mice also showed an accumulation of IgG1(+) memory B cells expressing high amounts of CD80 and the expansion of CD28-expressing CD4(+) Th cells. Blocking T cell-B cell interaction and GC formation completely prevented the fatal lymphoproliferation. Thus, Fas-mediated selection of GC B cells and the resulting memory B cell compartment is essential for maintaining the homeostasis of both T and B lymphocytes.
Campbell Family Institute for Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada. zhenyuehao@gmail.com
Zhenyue
Z
Hao
Gordon S
GS
Duncan
Jane
J
Seagal
Yu-Wen
YW
Su
Claire
C
Hong
Jillian
J
Haight
Nien-Jung
NJ
Chen
Andrew
A
Elia
Andrew
A
Wakeham
Wanda Y
WY
Li
Jennifer
J
Liepa
Geoffrey A
GA
Wood
Stefano
S
Casola
Klaus
K
Rajewsky
Tak W
TW
Mak
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019014:fas Receptor / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*
D015703:Antigens, CD; D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D019014:fas Receptor