BTLA Interaction with HVEM Expressed on CD8+ T Cells Promotes Survival and Memory Generation in Response to a Bacterial Infection

Marcos W Steinberg,Yiran Wang-Zhu,Hilde Cheroutre,Carl F Ware,Mitchell Kronenberg,Yujun Huang,George Kassiotis

doi:10.1371/journal.pone.0077992

Abstract

The B and T lymphocyte attenuator (BTLA) is an Ig super family member that binds to the herpes virus entry mediator (HVEM), a TNF receptor super family (TNFRSF) member. Engagement of BTLA by HVEM triggers inhibitory signals, although recent evidence indicates that BTLA also may act as an activating ligand for HVEM. In this study, we reveal a novel role for the BTLA-HVEM pathway in promoting the survival of activated CD8+ T cells in the response to an oral microbial infection. Our data show that both BTLA- and HVEM-deficient mice infected with Listeria monocytogenes had significantly reduced numbers of primary effector and memory CD8+ T cells, despite normal proliferation and expansion compared to controls. In addition, blockade of the BTLA-HVEM interaction early in the response led to significantly reduced numbers of antigen-specific CD8+ T cells. HVEM expression on the CD8+ T cells as well as BTLA expression on a cell type other than CD8+ T lymphocytes, was required. Collectively, our data demonstrate that the function of the BTLA-HVEM pathway is not limited to inhibitory signaling in T lymphocytes, and instead, that BTLA can provide crucial, HVEM-dependent signals that promote survival of antigen activated CD8+ T cell during bacterial infection.

Highlights

During acute microbial infections, antigen-specific naıve T cells recognize foreign antigens (Ag), undergo proliferative expansion, differentiate and carry out effector functions
To investigate the role of B and T lymphocyte attenuator (BTLA) in CD8+ T cell responses during an acute bacterial infection, WT or Btla2/2 mice were orally infected with recombinant Listeria monocytogenesexpressing ovalbumin (LM-OVA)
We report the surprising finding that during oral infection with intracellular bacteria, Listeria monocytogenes, the BTLA-herpesvirus entry mediator (HVEM) pathway plays a critical role in the adaptive immune system by promoting the survival of antigen-specific CD8+ T cells

Summary

Introduction

Antigen-specific naıve T cells recognize foreign antigens (Ag), undergo proliferative expansion, differentiate and carry out effector functions. This antigen-specific population undergoes a precipitous decline, but the surviving cells constitute the population of protective memory T lymphocytes. In addition to the binding to BTLA, HVEM serves as a receptor for four other ligands. It can bind two members of the TNF super family; LIGHT (TNFSF14) and lymphotoxin a (LTa) its binding with LTa is relatively weak [5]. CD160 was identified as a second Ig-domain containing molecule able to bind HVEM [8]

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Results

Conclusion