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Review
. 2017 Mar;276(1):26-39.
doi: 10.1111/imr.12521.

The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3

Murali Janakiram  1   2   3 , Urvi A Shah  1   2 , Weifeng Liu  4 , Aimin Zhao  5 , Mark P Schoenberg  6 , Xingxing Zang  1   2   3   6
Affiliations
Review

The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3

Murali Janakiram et al. Immunol Rev. 2017 Mar.

Abstract

The B7-CD28 family of ligands and receptors play important roles in T-cell co-stimulation and co-inhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules (B7-H3 [CD276], B7x [B7-H4/B7S1], and HHLA2 [B7H7/B7-H5]/TMIGD2 [IGPR-1/CD28H]) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7-H3, B7x, HHLA2, and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, transplantation, and infection. Various immunotherapeutical approaches are emerging including antagonistic monoclonal antibodies and agonistic fusion proteins to inhibit or potentiate these molecules and pathways in cancers and autoimmune diseases.

Keywords: B7-H3; B7x; HHLA2; TMIGD2; immune checkpoint; immunotherapy.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Structures of B7-H3, B7x and PD-L1
(A) Overall structure of the dimeric mB7H3 in the crystal (PDB entry 4I0K). The strands from each monomeric mB7H3 are colored and labeled differently. (B) The generated model of monomeric mB7H3 based on the crystal structure from PDB entry 4I0K. (C) The structure of the hB7x IgV domain (PDB entry 4GOS). (D) Superimposition of the monomeric mB7H3, hB7x and hPD-L1 (PD-L1 is from A chain of the PDB entry 3BIK). The disulfide bonds, carbohydrates and the connecting Asn residues are shown as sticks.
Figure 2
Figure 2. The third group of the B7-CD28 immune checkpoint family in the human cancer microenvironment
B7-H3 dampens (red broken line) NK cells and T cells, and may reprogram metabolism in cancer cells. B7x inhibits T cells and potentiates (green broken line) myeloid derived suppressor cells (MDSC). HHLA2 restricts T cells and may promote angiogenesis through its receptor TMIGD2 on endothelial cells. Receptors for B7x and B7-H3 molecules have not yet been identified.
See this image and copyright information in PMC

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