Abstract
B and T lymphocyte attenuator (BTLA), like its relative programmed cell death-1 (PD-1), is a receptor that negatively regulates murine T cell activation. However, its expression and function on human T cells is currently unknown. We report in this study on the expression of BTLA in human T cell subsets as well as its regulation on virus-specific T cells during primary human CMV infection. BTLA is expressed on human CD4(+) T cells during different stages of differentiation, whereas on CD8(+) T cells, it is found on naive T cells and is progressively downregulated in memory and differentiated effector-type cells. During primary CMV infection, BTLA was highly induced on CMV-specific CD8(+) T cells immediately following their differentiation from naive cells. After control of CMV infection, BTLA expression went down on memory CD8(+) cells. Engagement of BTLA by mAbs blocked CD3/CD28-mediated T cell proliferation and Th1 and Th2 cytokine secretion. Finally, in vitro blockade of the BTLA pathway augmented, as efficient as anti-PD-1 mAbs, allogeneic as well as CMV-specific CD8(+) T cell proliferation. Thus, our results suggest that, like PD-1, BTLA provides a potential target for enhancing the functional capacity of CTLs in viral infections.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / biosynthesis
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Antigens, CD / physiology
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / physiology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / pathology
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CD4-Positive T-Lymphocytes / virology*
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / virology*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cells, Cultured
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Cytomegalovirus / immunology*
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Cytomegalovirus / pathogenicity
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Cytomegalovirus Infections / immunology
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Cytomegalovirus Infections / pathology
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Cytomegalovirus Infections / prevention & control
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Cytotoxicity, Immunologic / genetics
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Down-Regulation / genetics
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Down-Regulation / immunology
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Epitopes, T-Lymphocyte / immunology*
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Female
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Humans
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred BALB C
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Programmed Cell Death 1 Receptor
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Receptors, Immunologic / antagonists & inhibitors
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Receptors, Immunologic / biosynthesis*
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Receptors, Immunologic / genetics*
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Resting Phase, Cell Cycle / genetics
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Resting Phase, Cell Cycle / immunology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / pathology
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T-Lymphocytes, Cytotoxic / virology
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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Antigens, CD
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Apoptosis Regulatory Proteins
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BTLA protein, human
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Epitopes, T-Lymphocyte
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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Receptors, Immunologic