Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis

Sarah L. May, Qing Zhou, Mitzi Lewellen, Cristan M. Carter, David Coffey, Steven L. Highfill, Christoph M. Bucher, Ilze Matise, Herbert C. Morse, M. Gerard O'Sullivan, Melissa Schutten, Charles Johnson, Donald Bellgrau, Bruce R. Blazar, Jaime F. Modiano

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere100629
JournalPLoS One
Volume9
Issue number6
DOIs
StatePublished - Jun 19 2014

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T-cells
carcinogenesis
Carcinogenesis
T-lymphocytes
T-Lymphocytes
Knockout Mice
mice
Chemical activation
Regulatory T-Lymphocytes
Lymphocytes
Homeostasis
B-Lymphocytes
B-lymphocytes
homeostasis
lymphocytes
Cells
Data storage equipment
Growth
Neoplasms
cells

Cite this

Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis. / May, Sarah L.; Zhou, Qing; Lewellen, Mitzi; Carter, Cristan M.; Coffey, David; Highfill, Steven L.; Bucher, Christoph M.; Matise, Ilze; Morse, Herbert C.; O'Sullivan, M. Gerard; Schutten, Melissa; Johnson, Charles; Bellgrau, Donald; Blazar, Bruce R.; Modiano, Jaime F.

In: PLoS One, Vol. 9, No. 6, e100629, 19.06.2014.

Research output: Contribution to journalArticle

May, SL, Zhou, Q, Lewellen, M, Carter, CM, Coffey, D, Highfill, SL, Bucher, CM, Matise, I, Morse, HC, O'Sullivan, MG, Schutten, M, Johnson, C, Bellgrau, D, Blazar, BR & Modiano, JF 2014, 'Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis', PLoS One, vol. 9, no. 6, e100629. https://doi.org/10.1371/journal.pone.0100629
May SL, Zhou Q, Lewellen M, Carter CM, Coffey D, Highfill SL et al. Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis. PLoS One. 2014 Jun 19;9(6). e100629. https://doi.org/10.1371/journal.pone.0100629
May, Sarah L. ; Zhou, Qing ; Lewellen, Mitzi ; Carter, Cristan M. ; Coffey, David ; Highfill, Steven L. ; Bucher, Christoph M. ; Matise, Ilze ; Morse, Herbert C. ; O'Sullivan, M. Gerard ; Schutten, Melissa ; Johnson, Charles ; Bellgrau, Donald ; Blazar, Bruce R. ; Modiano, Jaime F. / Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis. In: PLoS One. 2014 ; Vol. 9, No. 6.
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