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

Summary

The B7-CD28 family of ligands and receptors play important roles in T cell costimulation and coinhibition. 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.