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PLoS One. 2013 Oct 29;8(10):e77991. doi: 10.1371/journal.pone.0077991. eCollection 2013.

CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA.

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  • 1Department of Pathology, Immunology & Laboratory Medicine, University of Florida, Gainesville, Florida, United States of America ; La Jolla Institute for Allergy and Immunology, Divisions of Immune Regulation, San Diego, California, United States of America.

Abstract

Defining the molecular interactions required to program activated CD8 T cells to survive and become memory cells may allow us to understand how to augment anti-viral immunity. HVEM (herpes virus entry mediator) is a member of the tumor necrosis factor receptor (TNFR) family that interacts with ligands in the TNF family, LIGHT and Lymphotoxin-α, and in the Ig family, B and T lymphocyte attenuator (BTLA) and CD160. The Ig family members initiate inhibitory signaling when engaged with HVEM, but may also activate survival gene expression. Using a model of vaccinia virus infection, we made the unexpected finding that deficiency in HVEM or BTLA profoundly impaired effector CD8 T cell survival and development of protective immune memory. Mixed adoptive transfer experiments indicated that BTLA expressed in CD8α+ dendritic cells functions as a trans-activating ligand that delivers positive co-signals through HVEM expressed in T cells. Our data demonstrate a critical role of HVEM-BTLA bidirectional cosignaling system in antiviral defenses by driving the differentiation of memory CD8 T cells.

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