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      Tbata modulates thymic stromal cell proliferation and thymus function

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          Abstract

          By inhibiting Nedd8, Tbata suppresses thymic epithelial cell proliferation and thymus size in mice.

          Abstract

          Niche availability provided by stromal cells is critical to thymus function. Thymi with diminished function contain fewer stromal cells, whereas thymi with robust function contain proliferating stromal cell populations. Here, we show that the thymus, brain, and testes–associated gene ( Tbata; also known as SPATIAL) regulates thymic epithelial cell (TEC) proliferation and thymus size. Tbata is expressed in thymic stromal cells and interacts with the enzyme Uba3, thereby inhibiting the Nedd8 pathway and cell proliferation. Thymi from aged Tbata-deficient mice are larger and contain more dividing TECs than wild-type littermate controls. In addition, thymic reconstitution after bone marrow transplantation occurred more rapidly in Rag2 −/−Tbata −/− mice than in Rag2 −/−Tbata +/+ littermate controls. These findings suggest that Tbata modulates thymus function by regulating stromal cell proliferation via the Nedd8 pathway.

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          Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells.

          Kelli L. Boyd, Andrew M. Lew, Tomoo Ueno … (2006)
          Despite the importance of thymic stromal cells to T-cell development, relatively little is known about their biology. Here, we use single-cell analysis of stromal cells to analyze extensive changes in the number and composition of thymic stroma throughout life, revealing a surprisingly dynamic population. Phenotypic progression of thymic epithelial subsets was assessed at high resolution in young mice to provide a developmental framework. The cellular and molecular requirements of adult epithelium were studied, using various mutant mice to demonstrate new cross talk checkpoints dependent on RelB in the cortex and CD40 in the medulla. With the use of Ki67 and BrdU labeling, the turnover of thymic epithelium was found to be rapid, but then diminished on thymic involution. The various defects in stromal turnover and composition that accompanied involution were rapidly reversed following sex steroid ablation. Unexpectedly, mature cortical and medullary epithelium showed a potent capacity to stimulate naive T cells, comparable to that of thymic dendritic cells. Overall, these studies show that the thymic stroma is a surprisingly dynamic population and may have a more direct role in negative selection than previously thought.
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            Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity.

            Dimitris P Xirodimas, David Lane, Ronald Hay … (2004)
            The only reported role for the conjugation of the NEDD8 ubiquitin-like molecule is control of the activity of SCF ubiquitin ligase complexes. Here, we show that the Mdm2 RING finger E3 ubiquitin ligase can also promote NEDD8 modification of the p53 tumor suppressor protein. Mdm2 is itself modified with NEDD8 with very similar characteristics to the autoubiquitination activity of Mdm2. By using a cell line (TS-41) with a temperature-sensitive mutation in the NEDD8 conjugation pathway and a p53 mutant that cannot be NEDDylated (3NKR), we demonstrate that Mdm2-dependent NEDD8 modification of p53 inhibits its transcriptional activity. These findings expand the role for Mdm2 as an E3 ligase, providing evidence that Mdm2 is a common component of the ubiquitin and NEDD8 conjugation pathway and indicating the diverse mechanisms by which E3 ligases can control the function of substrate proteins.
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              Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire

              Daniel Gray, Jakub Abramson, Christophe Benoist … (2007)
              Expression of autoimmune regulator (Aire) by thymic medullary epithelial cells (MECs) is critical for central tolerance of self. To explore the mechanism by which such a rare cell population imposes tolerance on the large repertoire of differentiating thymocytes, we examined the proliferation and turnover of Aire+ and Aire− MEC subsets through flow cytometric analysis of 5-bromo-2′deoxyuridine (BrdU) incorporation. The Aire+ MEC subset was almost entirely postmitotic and derived from cycling Aire− precursors. Experiments using reaggregate thymic organ cultures revealed the presence of such precursors among Aire− MECs expressing low levels of major histocompatibility complex class II and CD80. The kinetics of BrdU decay showed the Aire+ population to have a high turnover. Aire did not have a direct impact on the division of MECs in vitro or in vivo but, rather, induced their apoptosis. We argue that these properties strongly favor a “terminal differentiation” model for Aire function in MECs, placing strict temporal limits on the operation of any individual Aire+ MEC in central tolerance induction. We further speculate that the speedy apoptosis of Aire-expressing MECs may be a mechanism to promote cross-presentation of the array of peripheral-tissue antigens they produce.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Exp Med
                Journal ID (iso-abbrev): J. Exp. Med
                Journal ID (hwp): jem
                Title: The Journal of Experimental Medicine
                Publisher: The Rockefeller University Press
                ISSN (Print): 0022-1007
                ISSN (Electronic): 1540-9538
                Publication date (Print): 25 October 2010
                Volume: 207
                Issue: 11
                Pages: 2521-2532
                Affiliations
                [1 ]Experimental Transplantation Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
                [2 ]Department of Neurology, 6109E Neuroscience Research Building, University of North Carolina, Chapel Hill, NC 27599
                [3 ]Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892
                Author notes
                CORRESPONDENCE Francis A. Flomerfelt: flomerff@ 123456mail.nih.gov
                Article
                Publisher ID: 20092759
                DOI: 10.1084/jem.20092759
                PMC ID: 2964569
                PubMed ID: 20937703
                SO-VID: 37ac3596-f8ca-4d1f-a6af-b2ac2aa6bea3
                Copyright statement: Copyright @ 2010
                License:

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                Date received : 24 December 2009
                Date accepted : 7 September 2010
                Categories
                Subject: Article

                ScienceOpen disciplines: Medicine
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                ScienceOpen disciplines: Medicine

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