title: HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function.
abstract: T-cell costimulation and coinhibition generated by engagement of the B7 family and their receptor CD28 family are of central importance in regulating the T-cell response, making these pathways very attractive therapeutic targets. Here we describe HERV-H LTR-associating protein 2 (HHLA2) as a member of the B7 family that shares 10-18% amino acid identity and 23-33% similarity to other human B7 proteins and phylogenetically forms a subfamily with B7x and B7-H3 within the family. HHLA2 is expressed in humans but not in mice, which is unique within the B7 and CD28 families. HHLA2 protein is constitutively expressed on the surface of human monocytes and is induced on B cells after stimulation with LPS and IFN-γ. HHLA2 does not interact with other known members of the CD28 family or the B7 family, but does bind a putative receptor that is constitutively expressed not only on resting and activated CD4 and CD8 T cells but also on antigen-presenting cells. HHLA2 inhibits proliferation of both CD4 and CD8 T cells in the presence of T-cell receptor signaling. In addition, HHLA2 significantly reduces cytokine production by T cells including IFN-γ, TNF-α, IL-5, IL-10, IL-13, IL-17A, and IL-22. Thus, we have identified a unique B7 pathway that is able to inhibit human CD4 and CD8 T-cell proliferation and cytokine production. This unique human T-cell coinhibitory pathway may afford unique strategies for the treatment of human cancers, autoimmune disorders, infection, and transplant rejection and may help to design better vaccines.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Zhao
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Chinai
authors.forename: Susan
authors.initials: S
authors.lastname: Buhl
authors.forename: Lisa
authors.initials: L
authors.lastname: Scandiuzzi
authors.forename: Anjana
authors.initials: A
authors.lastname: Ray
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Jeon
authors.forename: Kim C
authors.initials: KC
authors.lastname: Ohaegbulam
authors.forename: Kaya
authors.initials: K
authors.lastname: Ghosh
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhao
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Scharff
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060887:B7 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D019143:Evolution, Molecular; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid
chemical_list: D060887:B7 Antigens; D016207:Cytokines; C400341:HHLA2 protein, human; D007136:Immunoglobulins; D008070:Lipopolysaccharides; D008164:Luminescent Proteins