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CHaPTEr 9 Cytokines and Cytokine Receptors 143

is synthesized as a type II membrane protein and is expressed antibodies against CD40 with possible applications to treat
on activated B cells, T cells, and NK cells. Fas-induced apoptosis transplantation and autoimmune diseases have been developed. 52
can play an essential role in the termination of T-cell responses,
particularly in the peripheral immune system. Fas can also play Other TNF-Family Cytokines
a key role in the induction of cell death by cytotoxic T cells Other members of the TNFR family play various roles in the
(CTLs) and NK cells (Chapter 17), where it functions in conjunc- development and function of the immune system. OX-40, CD27,
tion with perforin. Nonapoptotic functions of FasL include CD30, and 4-1BB can mediate costimulation of T-cell activation.
lymphocyte costimulation and T-cell differentiation into short- The TNF family ligand BAFF (BlyS/TALL1/TNFSF13B) promotes
lived effector memory cells. 49,50 B-cell maturation and antibody secretion and can bind three
distinct receptors, TACI (TNFRSF13B), BADD-R (TNFRSF13C),
CD40 Ligand and CD40 and BCMA (TNFRSF17).
CD40 is expressed by a variety of cell types, including B cells,
DCs, monocytes, macrophages, and endothelial cells. It plays a Signaling
major costimulatory role in B-cell differentiation and recombina- The TNF receptor superfamily can be divided into three sub-
tion and promotes survival through the induction of BCL-2 families on the basis of the types of intracellular signaling
family members. Studies of both CD40-deficient mice and patients molecules recruited (e.g., FAS-associated death domain [FADD],
with hyper-IgM syndrome (Chapter 34) reveal that its function TNF receptor-associated death domain [TRADD], or TNF
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extends beyond the humoral immune response, with CD40 receptor–associated factor [TRAF]) (Fig. 9.5). The cytoplasmic
signaling also playing a role in cell-mediated immunity. CD40 domains of several receptors, including death receptor 3 (DR3),
ligand (CD154) is a 39-kDa protein expressed by activated CD4 DR4, DR5, TNFR1, and FAS contain a conserved ≈80-amino
T cells that can bind to and activate CD40 by cell–cell contact. acid motif termed the death domain (DD). This element is
CD40L on T cells triggers antigen-presenting cell (APC) required for recruitment of DD-containing adaptor molecules
activation, including upregulation of the CD28 ligands B7-1 and that are involved in the initiation of apoptotic cell death (Chapter
B7-2. This indirectly boosts costimulation of the T-cell response. 13). For this reason, these receptors have been termed “death
Because of its critical role in mediating T-cell help for B-cell class receptors.” The function of a number of death receptors can be
switching and autoantibody formation, blocking CD40L/CD40 regulated by decoy receptors. These are cell surface molecules
interactions has been a therapeutic goal in autoimmune diseases. that bind ligand but lack functional intracellular domains. Other
Clinical trials of a blocking anti-CD40L antibody in SLE showed TNF receptor superfamily receptors that lack death domains
promising results but were halted because of thrombotic events, (e.g., CD27, CD30, CD40, HVEM, TNFR2, LT-βR, OX-40, and
likely resulting from the off-target effects of these antibodies 4-1BB) associate with different types of adapter molecules, most
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on CD40L expressed on platelets. More recently, antagonistic notably members of the TRAF family.

TNFR1 TNFR2

DD RIP
TRADD TRAF2 cIAP TRAF1
FADD
NIK

IKK-α IKK-α
Caspase-8
P
IκB IκB
NF-κB
Caspase-3
NF-κB
Apoptosis Survival
FIG 9.5 The role of the death domain (DD)– and death effector domain (DED)–containing molecules
(e.g., Caspase-8) in signaling by tumor necrosis factor receptor 1 (TNFR1) and TNFR2.