The in vivo function of a noncanonical TRAF2-binding domain in the C-terminus of CD40 in driving B-cell growth and differentiation.
The recruitment of tumor necrosis factor receptor-associated factors (TRAFs) 1, 2, 3, 5, and 6 to the CD40 cytoplasmic tail upon CD40 trimerization results in downstream signaling events that ultimately lead to CD40-dependent, thymus-dependent (TD) humoral immune responses. Previously, we have shown signaling through the C-terminal tail of CD40 in the absence of canonical TRAF-binding sites is capable of signaling through an alternative TRAF2-binding site. Here, we demonstrate that B cells from mice harboring CD40 with only the C-terminal tail can activate both canonical and noncanonical NFkappaB signaling pathways. Moreover, while lacking germinal center formation, several hallmarks of humoral immune responses including clonal B-cell activation/expansion, antibody isotype switching, and affinity maturation remain normal. This study demonstrates a new functional domain in CD40 that controls critical aspects of B-cell immunity in an in vivo setting.
Lu
Li-Fan
LF
Department of Microbiology and Immunology, Dartmouth Medical School and the Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
Ahonen
Cory L
CL
Lind
Evan F
EF
Raman
Vanitha S
VS
Cook
W James
WJ
Lin
Ling-Li
LL
Noelle
Randolph J
RJ
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology*; D001665:Binding Sites; D019013:CD40 Antigens / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*
D019013:CD40 Antigens; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2