title: Pro-apoptotic protein Noxa regulates memory T cell population size and protects against lethal immunopathology.
abstract: Memory T cells form a highly specific defense layer against reinfection with previously encountered pathogens. In addition, memory T cells provide protection against pathogens that are similar, but not identical to the original infectious agent. This is because each T cell response harbors multiple clones with slightly different affinities, thereby creating T cell memory with a certain degree of diversity. Currently, the mechanisms that control size, diversity, and cross-reactivity of the memory T cell pool are incompletely defined. Previously, we established a role for apoptosis, mediated by the BH3-only protein Noxa, in controlling diversity of the effector T cell population. This function might positively or negatively impact T cell memory in terms of function, pool size, and cross-reactivity during recall responses. Therefore, we investigated the role of Noxa in T cell memory during acute and chronic infections. Upon influenza infection, Noxa(-/-) mice generate a memory compartment of increased size and clonal diversity. Reinfection resulted in an increased recall response, whereas cross-reactive responses were impaired. Chronic infection of Noxa(-/-) mice with mouse CMV resulted in enhanced memory cell inflation, but no obvious pathology. In contrast, in a model of continuous, high-level T cell activation, reduced apoptosis of activated T cells rapidly led to severe organ pathology and premature death in Noxa-deficient mice. These results establish Noxa as an important regulator of the number of memory cells formed during infection. Chronic immune activation in the absence of Noxa leads to excessive accumulation of primed cells, which may result in severe pathology.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. Felix.Wensveen@gmail.com
authors.forename: Felix M
authors.initials: FM
authors.lastname: Wensveen
authors.forename: Paul L
authors.initials: PL
authors.lastname: Klarenbeek
authors.forename: Klaas P J M
authors.initials: KP
authors.lastname: van Gisbergen
authors.forename: Maria F
authors.initials: MF
authors.lastname: Pascutti
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Derks
authors.forename: Barbera D C
authors.initials: BD
authors.lastname: van Schaik
authors.forename: Anja
authors.initials: A
authors.lastname: Ten Brinke
authors.forename: Niek
authors.initials: N
authors.lastname: de Vries
authors.forename: Durdica
authors.initials: D
authors.lastname: Cekinovic
authors.forename: Stipan
authors.initials: S
authors.lastname: Jonjic
authors.forename: René A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D060966:Clonal Selection, Antigen-Mediated; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology; D015329:Gene Rearrangement, T-Lymphocyte; D007156:Immunologic Memory; D008136:Longevity / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012008:Recurrence; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D014781:Viscera / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2