B7-H5 costimulates human T cells via CD28H

Abstract

The B7/CD28 family has profound modulatory effects in immune responses and constitutes important targets for the development of novel therapeutic drugs against human diseases. Here we describe a new CD28 homolog (CD28H) that has unique functions in the regulation of the human immune response and is absent in mice. CD28H is constitutively expressed on all naive T cells. Repetitive antigenic exposure, however, induces a complete loss of CD28H on many T cells, and CD28H-negative T cells have a phenotype of terminal differentiation and senescence. After extensive screening in a receptor array, a B7-like molecule, B7 homolog 5 (B7-H5), was identified as a specific ligand for CD28H. B7-H5 is constitutively found in macrophages and could be induced on dendritic cells. The B7-H5/CD28H interaction co-stimulates human T cell growth and cytokine production, selectively via an AKT-dependent signaling cascade. Our study identifies a novel co-stimulatory pathway regulating human T cell responses.

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

“…Given the promising results obtained with second-generation antibodies like anti-PD-L1 in the treatment of advanced, treatment-refractory cancers in recent clinical trials, the B7 family of co-inhibitory molecules are being closely watched as potential immune checkpoint cancer therapeutic targets, particularly B7-H5 and B7-H7. 7,10,11 Here, we provide an overview of the 10 currently known B7 family members, under a unified nomenclature based on previous studies. Our phylogenetic tree of human B7 was generated using MEGA and was divided into three groups: B7-H1 and B7-DC (which is consistent with reports from Zhao et al 16 ); B7-H5; and the remaining members as the third group.…”

“…Additionally, there has been some confusion in the literature regarding the naming of B7-H5 and B7-H7. 11,17 Here, we present a unified nomenclature of the B7 family according to the NCBI database.…”

Emerging Targets in Cancer Immunotherapy: Beyond CTLA-4 and PD-1

“…It was shown to inhibit proliferation of CD4 and CD8 T cells in the presence of TCR signaling as well as T-cell cytokine production [66]. TMIGD2, also called CD28H or IGPR-1, is identified as one of the receptors for HHLA2 [67,68]. IGPR-1 was initially reported to be an adhesion molecule involved in angiogenesis [68].…”

“…HHLA2 is another member of the B7 family that modulates T-cell function [66,67]. It is expressed on monocytes and induced on CD19 positive B cells.…”

CD28 family of receptors inter-connect in the regulation of T-cells

“…The CD28 homologue (CD28H) [37] is one such co-receptor. It is also known as the transmembrane and immunoglobulin domain-containing protein 2 variant 2 (TMIGD2) [35] ] or immunoglobulin-containing and proline-rich receptor-1 (IGPR-1) [36] and shares 10% sequence homology with CD28, ICOS, CTLA-4 and PD-1 [37] . CD28H is expressed in thymus, lung, heart and kidney [36] and it is constitutively expressed in all naive T-cells as well as NK cells, and is down-regulated following repeated in-vitro stimulation.…”