Blocking HVEM–LIGHT interactions on T cells reduces the persistence of antigen-specific memory T cell populations after secondary expansion through decreased Akt activity and loss of Bcl-2 expression

Amit Kumar Mehta

Barnden

Bertram

Bradley

Browning

Carl Ware

Cheung

Croft

De Trez

Doherty

Duhen

Force

Fütterer

Gommerman

Gonzalo

Harrop

Hendriks

Klaus Pfeffer

Kuchroo

Lenz

London

Mackay

Mahajan

Marsters

Mauri

McKinstry

Michael Croft

Murphy

Naseem Khorram

Paula S. Norris

Pejman Soroosh

Purton

Rogers

Salek-Ardakani

Scheu

Seder

Sedy

Shaikh

Song

Stahl

Stefanie Scheu

Summers-DeLuca

Takanori So

Tamada

Taylor A. Doherty

Viola

Wang

Ware

Watanabe

Watts

Zhai

English

PubMed

Memory T helper cells (Th cells) play an important role in host defense against pathogens but also contribute to the pathogenesis of inflammatory disorders. We found that a soluble decoy lymphotoxin β receptor (LT-βR)–Fc, which can block tumor necrosis factor (TNF)–related ligands LIGHT (TNFSF14) and LT-αβ binding to the herpesvirus entry mediator (HVEM) and the LT-βR, inhibited the accumulation of memory Th2 cells after antigen encounter and correspondingly reduced inflammatory responses in vivo. Showing that this was a function of the receptor for LIGHT, antigen-specific memory CD4 T cells deficient in HVEM were also unable to persist, despite having a normal immediate response to recall antigen. HVEM−/− memory Th2 cells displayed reduced activity of PKB (protein kinase B; Akt), and constitutively active Akt rescued their survival and restored strong inflammation after antigen rechallenge. This was not restricted to Th2 memory cells as HVEM-deficient Th1 memory cells were also impaired in surviving after encounter with recall antigen. Furthermore, the absence of LIGHT on T cells recapitulated the defect seen with the absence of HVEM, suggesting that activated T cells communicate through LIGHT–HVEM interactions. Collectively, our results demonstrate a critical role of HVEM signals in the persistence of large pools of memory CD4 T cells.</jats:p

Crossref

The Journal of Experimental Medicine

Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations

Article helper 2 cells that drive lung inflammation.

B and T lymphocyte attenuator regulates T cell activa tion through interaction with herpesvirus entry mediator.

Blockade of LIGHT/LTbeta and CD40 signaling induces allospecific T cell anergy, preventing graftversushost disease.

CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling.

Constitutive expres sion of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction.

Defective TCR expression in transgenic mice constructed using cDNAbased alpha and betachain genes under the control of heterologous regu latory elements.

Expression of lym photoxinalphabeta on antigenspecific T cells is required for DC func tion.

Mouse T cells receive costimulatory signals from LIGHT, a TNF family mem ber.

Regulation of development and function of memory CD4 sub sets.

Signaling pathways of LIGHT induced macrophage migration and vas cular smooth muscle cell

T cell activation determined by T cell receptor number and tunable thresholds.

T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvi ronment.

Targeting the LIGHTHVEM pathway.

The in hibitory HVEMBTLA pathway counter regulates lymphotoxin re ceptor signaling to achieve homeostasis of dendritic cells.

The lymphotoxin beta receptor controls organogenesis and af finity maturation in peripheral lymphoid tissues.

The regulation of T cell homeostasis and au toimmunity by T cellderived LIGHT.

The role of herpesvirus entry mediator as a negative regulator of T cellmediated responses.

TNF/TNFR family members in costimulation of T cell re sponses.

Unconventional ligand activation of herpesvirus entry me diator signals cell survival.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3135347

Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations

Abstract

Similar works

Full text

Available Versions

Crossref