Costimulatory Molecules: B7/CD28 Family

T cells require two signals for optimal activation. The first signal is delivered to the T cell receptor (TCR) by processed antigen displayed by major histocompatibility complex (MHC) molecules; this antigen-dependent signal provides specificity to the immune response. The second signal, known as the costimulatory signal, is delivered to receptors on T cells by costimulatory molecules. These cell-surface molecules provide contextual information that influences the ensuing immune response. Costimulatory signals can have either stimulatory or inhibitory effects on T cells. As several interactions can occur throughout the activation and effector phases of the immune response, it appears that the overall balance between positive and negative costimulation directs the magnitude, location and type of response. Temporal and spatial regulation of expression of both costimulatory receptors and ligands leads to dynamic modulation of T cell priming, homing, and effector function. Importantly, these molecules potentially can be targeted for therapy to block undesirable immune activation, for example during autoimmune disease or organ transplant rejection, or to stimulate desired immune responses to combat cancer or infection. The best described costimulatory interactions are those in the B7/CD28 family. B7 family members typically act as ligands for CD28 receptor family members, although B7-1 and PD-L1 (both B7 family members) can also act as receptors themselves. There are also crossfamily interactions, such as B7-H3 binding to the TREM receptor family member TREM-like transcript-2 (TLT-2) and BTLA binding to HVEM . HVEM also binds to LIGHT (TNF superfamily, member 14) and to lymphotoxin α to stimulate T cell responses; HVEM can also bind to CD160, an Ig superfamily member, to inhibit T cell responses. Other members of the B7/CD28 family may still await discovery, and alternative receptors for known family members may exist. For example, there are data to suggest the existence of a stimulatory receptor for PD-L1 and PD-L2. B7-H3 may also interact with a putative inhibitory receptor on T cells in addition to the stimulatory TLT-2.

Ligand	Ligand Expression	Receptor/ Expression	Function of Receptor on T Cells	Implications for Human Disease
B7-1 (CD80)	Inducible: APCs (slower kinetics than B7-2), T cells	CD28 Constitutive: mouse (all T cells), human (95% of CD4+, 50% of CD8+ T cells), plasma cells, NK cells	Stimulation of naive and previously activated T cells upon TCR ligation: ↑ proliferation (↓ p27Kip1,↑ G1/S); ↑ cytokine production (↑ NFκB, ↑ IL2); ↑ survival (↑ Bcl-xL, ↑ survival of Tregs); ↑ glucose metabolism; provides T cell-dependent B cell help for class switching.	Blockade of pathway to treat autoimmune inflammatory diseases and for transplantation; active engagement to expand anti-tumor T cells and Tregs
B7-2 (CD86)	Constitutive at low levels; inducible: APCs, T cells
B7-1	Inducible: APCs (slower kinetics than B7-2), T cells	CTLA-4 (CD152) Inducible: T cells; constitutive: Tregs	Inhibition of TCR-dependent activation: ↓ proliferation (↑ p27Kip1, ↓ G1/S); ↓ cytokine production (↓ NFκB, ↓ IL2); CD28- dependent and -independent functions; promotes inhibitory function of Tregs.	Blockade of pathway in tumor immunotherapy; receptor polymorphisms linked with autoimmunity
B7-2	Constitutive at low levels; inducible: APCs, T cells
ICOS Ligand (B7-H2, CD275)	Induced by TNFα and IFNγ: APCs, T cells, fi broblasts, endothelium )	ICOS (CD278) Inducible: T cells (CD28- dependent and CD28- independent); constitutive: resting memory T cells, Tregs	ICOS (CD278) Inducible: T cells (CD28- dependent and CD28- independent); constitutive: resting memory T cells, Tregs	Receptor polymorphisms associated with immunodefi ciency and autoimmunity
PD-L1 (B7-H1, CD274)	Constitutive (mouse), induced by IFNα/β/γ: APCs, T cells, nonhematopoieitic cells; overexpressed in tumor cells	PD1 (CD279) Inducible: DCs, macrophages, placenta (human); overexpressed in tumor cells	Inhibition: ↓ TCR signals through recruitment of protein tyrosine phosphatases (most effective at low levels of TCR signaling); ↓ cytokine production (↓ IL2, IFNγ, TNFα); ↓ proliferation (↓ G1/S); ↓ cytokine production greater than ↓ proliferation; ↓ survival (↓ Bcl-xL); ↓ CTL-mediated lysis.	Active engagement induces tolerance; ↑ PD-L1 on human tumors associated with poor prognosis (potential for blockade as therapy); ↑ PD-1 on T cells associated with poorer function in chronic viral infection (potential for blockade as therapy)
PD-L2 (B7-DC, CD273)	Inducible: DCs, macrophages, placenta (human); overexpressed in tumor cells
B7-H3 (CD276)	Inducible: T cells, B cells, DCs, NK cells; overexpressed in tumor cells	TLT-2 (TREM receptor family; mouse only) Constitutive: CD8+ T cells, B cells, macrophages, DCs; inducible: CD4+ T cells	Stimulation of CD8+ T cells: ↑ proliferation; ↑ cytokine production (↑ IFNγ and IL2); blockade leads to ↓ contact hypersensitivity in vivo.	Stimulation of CD8+ T cells: ↑ proliferation; ↑ cytokine production (↑ IFNγ and IL2); blockade leads to ↓ contact hypersensitivity in vivo.
B7-H4 (B7S1, B7x)	Inducible: T cells, B cells, DCs, monocytes; overexpressed in tumor cells	Receptor not yet identifi ed Putatively inducible on T cells	Inhibition of T cell proliferation: ↓ cytokine production (↓ IL2 and IL4); blockade/knockdown leads to ↑ EAE and tumor cell apoptosis.	Potential role in tumor immunotherapy
BTNL2 (BTL-II)	Inducible: T cells, B cells	Receptor not yet identifi ed Putatively inducible on T cells	Inhibition of CD4+ T cell function in vitro: ↓ proliferation of CD4+ T cells; ↓ ICOSL-mediated cytokine production (↓ TNFα, IFNγ, IL2, IL4, IL6, IL10, and IL17); ↓ activity of AP1, NFAT, and NFκB.	Polymorphisms/mutations in BTNL2 gene associated with sarcoidosis and inclusion body myositis
HVEM (TNFRSF14)	Constitutive, ↓ upon activation: naive T cells, naive B cells, im- mature DCs, memory T and B cells, nonhematopoietic cells	BTLA (CD272) Inducible: T cells (↑ on anergic B cells CD160, LIGHT	Inhibition of CD4+ T cell proliferation: ↓ cytokine production (↓ IL2); defi ciency promotes EAE and allograft rejection in vivo;BTLA-defi cient mice develop autoimmune-like disease.	Pathway blockade enhances immune responses; one polymorphism associatedwith ↑ risk of rheumatoid arthritis

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