title: Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis.
abstract: Nfatc2 and Tob1 are intrinsic negative regulators of T cell activation. Nfatc2-deficient and Tob1-deficient T cells show reduced thresholds of activation; however, whether these factors have independent or overlapping roles in negative regulation of T cell responses has not been previously examined. Here, we show that Nfatc2 knockout (KO) but not Tob1 KO mice have age-associated accumulation of persistently activated T cells in vivo and expansion of the CD44+ memory cell compartment and age-associated lymphocytic infiltrates in visceral organs, without significant changes in numbers of CD4+CD25+Foxp3+ regulatory T cells (Treg). In vitro, CD4+CD25- "conventional" T cells (Tconvs) from both KO strains showed greater proliferation than wild type (WT) Tconvs. However, while Tregs from Nfatc2 KO mice retained normal suppressive function, Tregs from Tob1 KOs had enhanced suppressive activity. Nfatc2 KO Tconvs expanded somewhat more rapidly than WT Tconvs under conditions of homeostatic proliferation, but their accelerated growth capacity was negated, at least acutely, in a lymphoreplete environment. Finally, Nfatc2 KO mice developed a previously uncharacterized increase in B-cell malignancies, which was not accelerated by the absence of Tob1. The data thus support the prevailing hypothesis that Nfatc2 and Tob1 are non-redundant regulators of lymphocyte homeostasis.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States of America.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: May
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States of America.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Lewellen
authors.affiliation: Integrated Department of Immunology, School of Medicine, University of Colorado, Denver, Colorado, United States of America; University of Colorado Cancer Center, Aurora, Colorado, United States of America.
authors.forename: Cristan M
authors.initials: CM
authors.lastname: Carter
authors.affiliation: Integrated Department of Immunology, School of Medicine, University of Colorado, Denver, Colorado, United States of America; University of Colorado Cancer Center, Aurora, Colorado, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Coffey
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Highfill
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Bucher
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States of America.
authors.forename: Ilze
authors.initials: I
authors.lastname: Matise
authors.affiliation: National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland, United States of America.
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States of America.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Schutten
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Integrated Department of Immunology, School of Medicine, University of Colorado, Denver, Colorado, United States of America; University of Colorado Cancer Center, Aurora, Colorado, United States of America.
authors.forename: Donald
authors.initials: D
authors.lastname: Bellgrau
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States of America; Integrated Department of Immunology, School of Medicine, University of Colorado, Denver, Colorado, United States of America; University of Colorado Cancer Center, Aurora, Colorado, United States of America.
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology
chemical_list: D015704:CD4 Antigens; D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; C490903:Tob1 protein, mouse