B7-H2 Is a Costimulatory Ligand for CD28 in Human

Yao, Sheng; Zhu, Yuwen; Zhu, Gefeng; Augustine, Mathew M.; Zheng, Linghua; Goode, Diana J.; Broadwater, Megan; Ruff, William; Flies, Sarah J.; Xu, Huimin; Flies, Dallas B.; Luo, Liqun; Wang, Shengdian; Chen, Lieping

doi:10.1016/j.immuni.2011.03.014

Cited by 126 publications

(125 citation statements)

References 33 publications

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“…In summary, the optimal elaboration of secondary CD8 ϩ T E responses in the LCMV Arm model requires CD8 ϩ T M -expressed CD28 but surprisingly not host-expressed CD80/86. The most straightforward explanation for this unexpected phenomenon is the existence of a novel CD28 ligand in addition to CD80/86, and while investigations to this extent are currently ongoing, we note that a very recent report documented a new CD28 ligand, the B7 family member ICOSL/B7-H2, in humans but apparently not in mice (83).…”

Section: Cd80mentioning

confidence: 73%

“…5C versus 8B]), we have now obtained functional in vivo evidence that CD8 ϩ T M may productively interact with a novel CD28 ligand. In humans, such a ligand was recently identified (ICOSL/B7-H2), and while CD28-ICOSL interactions appear not to take place mice (83), it is not unreasonable to consider the possibility of other murine CD28 ligands among known or novel B7 family members (16).…”

Section: Discussionmentioning

confidence: 99%

“…A novel CD80 receptor has in fact been identified in both mice and humans (PD-L1/CD274/B7-H1), yet CD80 -PD-L1 interactions appear to promote inhibitory rather than activating T cell signals (12,13). Together with the recent identification of another costimulatory CD28 ligand in humans (ICOSL/B7-H2) and the description of the Trem-like transcript 2 protein (TLT2) as a potential CD276/ B7-H3 receptor (31,48,83), these observations clearly point toward more "promiscuous" receptor-ligand interactions within and beyond the B7 family that may well contribute to the regulation of antiviral T cell immunity under certain experimental and naturally occurring conditions.…”

mentioning

confidence: 97%

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Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

Eberlein

Davenport

Nguyen

et al. 2012

J Virol

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The lymphocytic choriomeningitis virus (LCMV) system constitutes one of the most widely used models for the study of infectious disease and the regulation of virus-specific T cell immunity. However, with respect to the activity of costimulatory and associated regulatory pathways, LCMV-specific T cell responses have long been regarded as relatively independent and thus distinct from the regulation of T cell immunity directed against many other viral pathogens. Here, we have reevaluated the contribution of CD28-CD80/86 costimulation in the LCMV system by use of CD80/86-deficient mice, and our results demonstrate that a disruption of CD28-CD80/86 signaling compromises the magnitude, phenotype, and/or functionality of LCMVspecific CD8 ؉ and/or CD4 ؉ T cell populations in all stages of the T cell response. Notably, a profound inhibition of secondary T cell immunity in LCMV-immune CD80/86-deficient mice emerged as a composite of both defective memory T cell development and a specific requirement for CD80 but not CD86 in the recall response, while a related experimental scenario of CD28-dependent yet CD80/86-independent secondary CD8 ؉ T cell immunity suggests the existence of a CD28 ligand other than CD80/ 86. Furthermore, we provide evidence that regulatory T cells (T REG s), the homeostasis of which is altered in CD80/86 ؊/؊ mice, contribute to restrained LCMV-specific CD8 ؉ T cell responses in the presence of CD80/86. Our observations can therefore provide a more coherent perspective on CD28-CD80/86 costimulation in antiviral T cell immunity that positions the LCMV system within a shared context of multiple defects that virus-specific T cells acquire in the absence of CD28-CD80/86 costimulation.T he generation of specific T cell immunity is governed by multiple determinants that shape the proliferative expansion and functional maturation of effector T cells (T E ) as well as their subsequent differentiation into memory T cells (T M ). Conceptualization of these processes permits the straightforward demarcation of T cell receptor (TCR)-peptide/major histocompatibility complex (MHC) interactions ("signal 1"), yet the simple notion of a defined "costimulus" required for the optimization of specific T cell responses, historically referred to as "signal 2," has been eroded by the realization that a multiplicity of diverse receptor-ligand interactions between T cells and antigen-presenting cells (APCs), soluble factors (e.g., cytokines), and specific temporospatial constraints operate in concert to control the eventual magnitude as well as the molecular, phenotypic, and functional properties of responding T E populations. Thus, it is the integration of signals derived from a large complex of stimulatory and inhibitory interactions that permits activated T cells the translation of minimal kinetic alterations into profound modifications of the ensuing T cell response (26,84). Insofar as these interactions produce a kinetic, quantitative, and/or qualitative enhancement of specific T cell immunity, individual components with...

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Section: Cd80mentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

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Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

Eberlein

Davenport

Nguyen

et al. 2012

J Virol

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“…144 This was the same molecule, ICOS-ligand (B7RP-1/B7h/ ICOS-L/CD275), and a later study showed that ICOS-L could bind and costimulate via CD28. 145 ICOS may play a role in maintaining durable immune reactions 146 and is expressed at particularly high levels in germinal center T cells or TFH (follicular helper) cells. 147,148 ICOS-L is constitutively expressed by APCs as well as diverse nonhematologic tissues 143 and down-regulated with ongoing inflammation, 149,150 in contrast to the activation-induced CD28 ligands CD80/CD86.…”

Section: Another Costimulatory B7 Pathway: Icos and B7-h2mentioning

confidence: 99%

The role of B7 family molecules in hematologic malignancy

Greaves

Gribben

2013

Blood

161

125

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IntroductionCancer and the immune system are fundamentally interrelated. 1,2 Cancer cells express tumor-specific aberrant antigens 3,4 and must therefore evade immune detection to survive, 5 either by inducing immunosuppression 2 or deriving survival signals from tumor-infiltrating immune cells. 6 T cell-mediated antitumor immunity 4 requires recognition of cancer-associated antigen by the major histocompatibility complex (MHC), and appropriate costimulatory and repressive secondary signals arising from complex interactions with other immune, stromal, and tumor cells. Dysfunction of costimulation pathways may contribute to failed antitumor immunity.The B7 system (Table 1) is one of the most important secondary signaling mechanisms and is essential in maintaining the delicate balance between immune potency and suppression of autoimmunity. Potential therapeutic applications include immune-boosting adjuvants to conventional anticancer therapy, hematopoietic stem cell transplantation (HSCT), antitumor vaccines, bioengineered T cells as well as attenuation of graft-versus-host disease (GVHD). The B7 family is only one aspect of a complex signaling network (Figures 1 and 2) that comprises other immunoglobulin superfamily (IGSF) members, the tumor necrosis factor superfamily (TNFRSF), chemokines, cytokines, and adhesion molecules. However, based on a substantial evidence base and a growing therapeutic armory, the B7 family requires particular attention, as summarized in Table 2.7 The standardized approach to nomenclature is the cluster of differentiation (CD), which has not yet been applied to all members of the family. While many researchers are more familiar with their original names, which are still widely used in the literature, for the purposes of this review, the CD designation is used wherever possible. B7 founder members CD80, CD28, and CD152 (CTLA-4)The first B7 family member was a molecule discovered on activated, proliferative splenic B lymphocytes, 7 and termed B7 in an early nomenclature convention attributed to B cell-defining markers. Subsequent cloning and sequencing of the B7 gene revealed sequence homology with IGSF members and expression in a variety of lymphoid malignancies. 8 B7 was found to bind CD28, 9 an IGSF member on T cells, which augmented their activation. [10][11][12] Further molecular profiling identified a CD28 homologue, CD152 (cytolytic T cell-associated sequence-4 [CTLA-4]), 13 which mapped to the same chromosomal region as CD28 14 and bound B7 more potently. 15 The B7 signal blockade using a CTLA-4.Ig construct led to suppression of humoral 16 and cellmediated immune responses, 17 while transfection of immunogenic murine melanoma cell lines with B7 enhanced antitumor immunity, which could be abrogated by CTLA-4.Ig. 18 Initial experiments suggested that both anti-CD28 and anti-CTLA-4 monoclonal antibodies (mAbs) were T-cell activators, 19 but contrary evidence showing a suppressive role for CTLA-4 soon emerged 20,21 and was conclusively demonstrated in Ctla-4 Ϫ/Ϫ mice, which rapidl...

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“…For comparison, the potency of abatacept, which blocks the CD28 pathway indirectly by binding to CD80 and CD86 molecules on the APC, is ∼2300 ng/ml (25 nM) in T cell proliferation (Table II). It has been reported that CD28 can also bind to ICOS ligand on APCs and act as a costimulus, with suboptimal concentrations of anti-CD3 mAb, to promote T cell proliferation (32). In assays in which suboptimal concentrations of immobilized anti-CD3 and ICOS ligand were coimmobilized at either 10 or 30 mg/ml, anti-CD28 dAb, at concentrations well above the IC 90 for inhibition of a DC-MLR, was unable to inhibit this response (data not shown).…”

Section: In Vitro Characterizationmentioning

confidence: 99%

A Monovalent Anti-Human CD28 Domain Antibody Antagonist: Preclinical Efficacy and Safety

Suchard

Davis

Kansal

et al. 2013

The Journal of Immunology

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Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 ± 14 ng/ml for inhibition of proliferation. The EC50 of 53 ± 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4–mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell–dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases.

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B7-H2 Is a Costimulatory Ligand for CD28 in Human

Cited by 126 publications

References 33 publications

Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

Multiple Layers of CD80/86-Dependent Costimulatory Activity Regulate Primary, Memory, and Secondary Lymphocytic Choriomeningitis Virus-Specific T Cell Immunity

The role of B7 family molecules in hematologic malignancy

A Monovalent Anti-Human CD28 Domain Antibody Antagonist: Preclinical Efficacy and Safety

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