title: Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations.
abstract: 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.
authors.affiliation: Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Pejman
authors.initials: P
authors.lastname: Soroosh
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Doherty
authors.forename: Takanori
authors.initials: T
authors.lastname: So
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Mehta
authors.forename: Naseem
authors.initials: N
authors.lastname: Khorram
authors.forename: Paula S
authors.initials: PS
authors.lastname: Norris
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Carl
authors.initials: C
authors.lastname: Ware
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
mesh_terms: D000818:Animals; D002470:Cell Survival; D005260:Female; D007156:Immunologic Memory; D007249:Inflammation / Q000209:etiology; D053259:Lymphotoxin beta Receptor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000502:physiology
chemical_list: C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011993:Recombinant Fusion Proteins; C506029:Tnfrsf14 protein, mouse; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D051057:Proto-Oncogene Proteins c-akt