B7-H2, also known as B7-related protein (B7RP1), ICOS Ligand, and CD275, is an approximately 60 kDa transmembrane glycoprotein in the B7 family of immune regulatory molecules (1). Mature cynomolgus B7-H2 consists of a 226 amino acid (aa) extracellular domain (ECD) with two immunoglobulin-like domains, a 21 aa transmembrane segment, and a 25 aa cytoplasmic domain (2, 3). Within the ECD, cynomolgus B7-H2 shares 94%, 50%, and 54% aa sequence identity with human, mouse, and rat B7-H2, respectively. Alternative splicing generates a long isoform that carries a 10 aa substitution for the 3 C-terminal residues in humans and a 27 aa substitution for the 2 C-terminal residues in mouse. B7-H2 is expressed on antigen presenting cells such as B cells, macrophages, monocytes, and dendritic cells
(2-6). B7-H2 binds to ICOS on activated T cells, leading to both positive and negative effects on immune responses including its own down-regulation (2, 4, 7). Mouse and human B7-H2 exhibit cross-species binding to ICOS (3, 6). The B7-H2 interaction with ICOS is co-stimulatory for T cell proliferation as well as the development of B cells, plasma cells, follicular helper T cells (Tfh) and germinal centers (2-4, 8, 9). In human but not in mouse, B7-H2 additionally binds to CD28 and CTLA4, and its interaction with CD28 can co-stimulate both human and mouse naïve T cells and regulatory T cells (Treg) (6). B7-H2 contributes to the development of allergic asthma by enhancing Th2 biased immune responses, limiting Th17 responses, and promoting eosinophilic infiltration into the lung (8, 10, 11). Its activation of ICOS on Treg limits pulmonary inflammation and airway hyperresponsiveness, promotes the development of inhalational tolerance, and impairs anti-tumor immunity (5, 12, 13). In contrast, its ligation of ICOS on Tfh cells can increase the severity of autoimmune symptoms (9). A soluble form of human B7-H2 is elevated in the circulation of patients with active systemic lupus erythematosus (14).In the thyroid, B7-H2 is up-regulated on thyrocytes during inflammation and promotes their proliferation and production of thryoid hormones (15). B7-H2 and ICOS expressed on ILC2 cells. B7-H2/ICOS interaction promoted cytokine production and survival in ILC2 cells through STAT5, suggesting that B7-H2/ICOS signaling pathway is critically involved in ILC2 function and homeostasis (16).