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HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Jun 11; Vol. 110 (24), pp. 9879-84. Date of Electronic Publication: 2013 May 28. - Publication Year :
- 2013
-
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.
- Subjects :
- 3T3 Cells
Amino Acid Sequence
Animals
Antigen-Presenting Cells metabolism
B-Lymphocytes drug effects
B-Lymphocytes immunology
B-Lymphocytes metabolism
B7 Antigens genetics
B7 Antigens immunology
B7 Antigens metabolism
CD4-Positive T-Lymphocytes metabolism
CD8-Positive T-Lymphocytes metabolism
Cell Line, Tumor
Cell Membrane metabolism
Cells, Cultured
Cytokines immunology
Cytokines metabolism
Cytoplasm metabolism
Evolution, Molecular
Flow Cytometry
Humans
Immunoglobulins genetics
Immunoglobulins metabolism
Leukocytes, Mononuclear immunology
Leukocytes, Mononuclear metabolism
Lipopolysaccharides immunology
Lipopolysaccharides pharmacology
Luminescent Proteins genetics
Luminescent Proteins metabolism
Mice
Mice, Inbred BALB C
Microscopy, Confocal
Molecular Sequence Data
Sequence Homology, Amino Acid
Antigen-Presenting Cells immunology
CD4-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes immunology
Immunoglobulins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 110
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 23716685
- Full Text :
- https://doi.org/10.1073/pnas.1303524110