Related Experiment Video
Updated: Apr 28, 2026
A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia
Published on: December 4, 2018
Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis
Sarah L May1, Qing Zhou2, Mitzi Lewellen1
1Masonic 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.
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.
Insights
Nuclear factor of activated T cells 2 (Nfatc2) and T-cell activation inhibitor 1 (Tob1) are key regulators of T cell activation. Nfatc2 deficiency, but not Tob1 deficiency, leads to T cell accumulation and B-cell malignancies in mice.
Area of Science:
- Immunology
- Cellular Biology
- Molecular Biology
Background:
- Nfatc2 and Tob1 are intrinsic negative regulators of T cell activation.
- The independent or overlapping roles of Nfatc2 and Tob1 in regulating T cell responses remain unclear.
Purpose of the Study:
- To investigate the distinct and overlapping roles of Nfatc2 and Tob1 in T cell regulation and lymphocyte homeostasis.
Main Methods:
- Comparison of T cell activation, proliferation, and regulatory function in Nfatc2 knockout (KO) and Tob1 KO mice.
- In vivo analysis of T cell populations, memory cell compartment, and organ infiltrates.
- In vitro assessment of T cell proliferation and regulatory T cell (Treg) suppressive activity.
- Evaluation of B-cell malignancies in KO mice.
Main Results:
- Nfatc2 KO mice, unlike Tob1 KO mice, exhibited age-associated accumulation of persistently activated T cells, expanded memory cell compartment, and organ lymphocytic infiltrates.
- Both Nfatc2 KO and Tob1 KO conventional T cells (Tconvs) showed increased proliferation in vitro.
- Tregs from Nfatc2 KO mice maintained normal suppressive function, while Tob1 KO Tregs displayed enhanced suppressive activity.
- Nfatc2 KO mice developed increased B-cell malignancies, independent of Tob1 absence.
Conclusions:
- Nfatc2 and Tob1 function as non-redundant regulators of lymphocyte homeostasis.
- Nfatc2 plays a critical role in preventing age-associated T cell activation and B-cell malignancies.
More Related Videos
Related Concept Videos
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
01:16TGF - β Signaling Pathway
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...