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Wei-Feng Yen, Ashutosh Chaudhry, Bharat Vaidyanathan, William T Yewdell, Joseph N Pucella, Rahul Sharma, Yulong Liang, Kaiyi Li, Alexander Y Rudensky, Jayanta Chaudhuri
DNA double-strand breaks (DSBs) serve as obligatory intermediates for Ig heavy chain (Igh) class switch recombination (CSR). The mechanisms by which DSBs are resolved to promote long-range DNA end-joining while suppressing genomic instability inherently associated with DSBs are yet to be fully elucidated. Here, we use a targeted short-hairpin RNA screen in a B-cell lymphoma line to identify the BRCT-domain protein BRIT1 as an effector of CSR. We show that conditional genetic deletion of BRIT1 in mice leads to a marked increase in unrepaired Igh breaks and a significant reduction in CSR in ex vivo activated splenic B cells...
July 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
Andrew G Levine, Alejandra Medoza, Saskia Hemmers, Bruno Moltedo, Rachel E Niec, Michail Schizas, Beatrice E Hoyos, Ekaterina V Putintseva, Ashutosh Chaudhry, Stanislav Dikiy, Sho Fujisawa, Dmitriy M Chudakov, Piper M Treuting, Alexander Y Rudensky
Adaptive immune responses are tailored to different types of pathogens through differentiation of naive CD4 T cells into functionally distinct subsets of effector T cells (T helper 1 (TH1), TH2, and TH17) defined by expression of the key transcription factors T-bet, GATA3, and RORγt, respectively. Regulatory T (Treg) cells comprise a distinct anti-inflammatory lineage specified by the X-linked transcription factor Foxp3 (refs 2, 3). Paradoxically, some activated Treg cells express the aforementioned effector CD4 T cell transcription factors, which have been suggested to provide Treg cells with enhanced suppressive capacity...
June 15, 2017: Nature
Andrew G Levine, Saskia Hemmers, Antonio P Baptista, Michail Schizas, Mehlika B Faire, Bruno Moltedo, Catherine Konopacki, Marc Schmidt-Supprian, Ronald N Germain, Piper M Treuting, Alexander Y Rudensky
The regulatory T cell (T reg cell) T cell receptor (TCR) repertoire is highly diverse and skewed toward recognition of self-antigens. TCR expression by T reg cells is continuously required for maintenance of immune tolerance and for a major part of their characteristic gene expression signature; however, it remains unknown to what degree diverse TCR-mediated interactions with cognate self-antigens are required for these processes. In this study, by experimentally switching the T reg cell TCR repertoire to a single T reg cell TCR, we demonstrate that T reg cell function and gene expression can be partially uncoupled from TCR diversity...
March 6, 2017: Journal of Experimental Medicine
Jason D Fontenot, Marc A Gavin, Alexander Y Rudensky
No abstract text is available yet for this article.
February 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Bharat Vaidyanathan, Ashutosh Chaudhry, William T Yewdell, Davide Angeletti, Wei-Feng Yen, Adam K Wheatley, Christopher A Bradfield, Adrian B McDermott, Jonathan W Yewdell, Alexander Y Rudensky, Jayanta Chaudhuri
Generation of cellular heterogeneity is an essential feature of the adaptive immune system. This is best exemplified during humoral immune response when an expanding B cell clone assumes multiple cell fates, including class-switched B cells, antibody-secreting plasma cells, and memory B cells. Although each cell type is essential for immunity, their generation must be exquisitely controlled because a class-switched B cell cannot revert back to the parent isotype, and a terminally differentiated plasma cell cannot contribute to the memory pool...
January 2017: Journal of Experimental Medicine
Ibrahim M Sektioglu, Rafael Carretero, Nadja Bulbuc, Tobias Bald, Thomas Tüting, Alexander Y Rudensky, Günter J Hämmerling
Elevated numbers of regulatory T cells (Treg) in patient tumors are known to inhibit efficient antitumor T-cell responses. To study the mechanisms controlling tumor rejection, we assessed different mouse models for Treg depletion. In Foxp3DTR knock-in mice, about 99% Treg depletion was achieved, resulting in complete rejection of transplanted HCmel12 melanomas in a CD8(+) T-cell-dependent way. In contrast, about 90% Treg depletion obtained in BAC transgenic Foxp3.LuciDTR4 mice failed to induce complete rejection of HCmel12 melanomas, demonstrating that residual Tregs were able to control CD8(+) T-cell responses against the tumor...
January 15, 2017: Cancer Research
George Plitas, Catherine Konopacki, Kenmin Wu, Paula D Bos, Monica Morrow, Ekaterina V Putintseva, Dmitriy M Chudakov, Alexander Y Rudensky
Regulatory T (Treg) cells reside in lymphoid organs and barrier tissues where they control different types of inflammatory responses. Treg cells are also found in human cancers, and studies in animal models suggest that they contribute to cancer progression. However, properties of human intratumoral Treg cells and those present in corresponding normal tissue remain largely unknown. Here, we analyzed features of Treg cells in untreated human breast carcinomas, normal mammary gland, and peripheral blood. Tumor-resident Treg cells were potently suppressive and their gene-expression pattern resembled that of normal breast tissue, but not of activated peripheral blood Treg cells...
November 15, 2016: Immunity
Takatoshi Chinen, Arun K Kannan, Andrew G Levine, Xiying Fan, Ulf Klein, Ye Zheng, Georg Gasteiger, Yongqiang Feng, Jason D Fontenot, Alexander Y Rudensky
Regulatory T cells (Treg cells), which have abundant expression of the interleukin 2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature indicates a key role for a simple network based on the consumption of IL-2 by Treg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the Treg cell lineage-specification factor Foxp3, which has confounded experimental efforts to understand the role of IL-2R expression and signaling in the suppressor function of Treg cells...
November 2016: Nature Immunology
George Plitas, Alexander Y Rudensky
The immune system of vertebrate animals has evolved to mount an effective defense against a diverse set of pathogens while minimizing transient or lasting impairment in tissue function that could result from the inflammation caused by immune responses to infectious agents. In addition, misguided immune responses to "self" and dietary antigens, as well as to commensal microorganisms, can lead to a variety of inflammatory disorders, including autoimmunity, metabolic syndrome, allergies, and cancer. Regulatory T cells expressing the X chromosome-linked transcription factor Foxp3 suppress inflammatory responses in diverse biological settings and serve as a vital mechanism of negative regulation of immune-mediated inflammation...
September 2, 2016: Cancer Immunology Research
Ushma S Neill
No abstract text is available yet for this article.
September 1, 2016: Journal of Clinical Investigation
Joris van der Veeken, Alvaro J Gonzalez, Hyunwoo Cho, Aaron Arvey, Saskia Hemmers, Christina S Leslie, Alexander Y Rudensky
Eukaryotic cells can "remember" transient encounters with a wide range of stimuli, inducing lasting states of altered responsiveness. Regulatory T (Treg) cells are a specialized lineage of suppressive CD4 T cells that act as critical negative regulators of inflammation in various biological contexts. Treg cells exposed to inflammatory conditions acquire strongly enhanced suppressive function. Using inducible genetic tracing, we analyzed the long-term stability of activation-induced transcriptional, epigenomic, and functional changes in Treg cells...
August 11, 2016: Cell
Ming O Li, Alexander Y Rudensky
Regulatory T cells (TReg cells), a specialized T cell lineage, have a pivotal function in the control of self tolerance and inflammatory responses. Recent studies have revealed a discrete mode of T cell receptor (TCR) signalling that regulates TReg cell differentiation, maintenance and function and that affects gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of TReg cells in the context of their function in health and disease...
April 2016: Nature Reviews. Immunology
Xiying Fan, Alexander Y Rudensky
Although they are classically viewed as continuously recirculating through the lymphoid organs and blood, lymphocytes also establish residency in non-lymphoid tissues, most prominently at barrier sites, including the mucosal surfaces and skin. These specialized tissue-resident lymphocyte subsets span the innate-adaptive continuum and include innate lymphoid cells (ILCs), unconventional T cells (e.g., NKT, MAIT, γδ T cells, and CD8αα(+) IELs), and tissue-resident memory T (T(RM)) cells. Although these diverse cell types differ in the particulars of their biology, they nonetheless exhibit important shared features, including a role in the preservation of tissue integrity and function during homeostasis, infection, and non-infectious perturbations...
March 10, 2016: Cell
Sunglim Cho, Cheng-Jang Wu, Tomoharu Yasuda, Leilani O Cruz, Aly Azeem Khan, Ling-Li Lin, Duc T Nguyen, Marina Miller, Hyang-Mi Lee, Ming-Ling Kuo, David H Broide, Klaus Rajewsky, Alexander Y Rudensky, Li-Fan Lu
Coordinated repression of gene expression by evolutionarily conserved microRNA (miRNA) clusters and paralogs ensures that miRNAs efficiently exert their biological impact. Combining both loss- and gain-of-function genetic approaches, we show that the miR-23∼27∼24 clusters regulate multiple aspects of T cell biology, particularly helper T (Th) 2 immunity. Low expression of this miRNA family confers proper effector T cell function at both physiological and pathological settings. Further studies in T cells with exaggerated regulation by individual members of the miR-23∼27∼24 clusters revealed that miR-24 and miR-27 collaboratively limit Th2 responses through targeting IL-4 and GATA3 in both direct and indirect manners...
February 8, 2016: Journal of Experimental Medicine
Alexander Yu Rudensky, Paula Preston-Hurlburt, Soon-Cheol Hong, Avlin Barlow, Charles A Janeway
No abstract text is available yet for this article.
February 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Julie-Ann Collins, Aram Rudenski, John Gibson, Luke Howard, Ronan O'Driscoll
The delivery of oxygen by arterial blood to the tissues of the body has a number of critical determinants including blood oxygen concentration (content), saturation (S O2 ) and partial pressure, haemoglobin concentration and cardiac output, including its distribution. The haemoglobin-oxygen dissociation curve, a graphical representation of the relationship between oxygen satur-ation and oxygen partial pressure helps us to understand some of the principles underpinning this process. Historically this curve was derived from very limited data based on blood samples from small numbers of healthy subjects which were manipulated in vitro and ultimately determined by equations such as those described by Severinghaus in 1979...
September 2015: Breathe
Yongqiang Feng, Joris van der Veeken, Mikhail Shugay, Ekaterina V Putintseva, Hatice U Osmanbeyoglu, Stanislav Dikiy, Beatrice E Hoyos, Bruno Moltedo, Saskia Hemmers, Piper Treuting, Christina S Leslie, Dmitriy M Chudakov, Alexander Y Rudensky
T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self-MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for 'self' are either eliminated through TCR-agonist-induced apoptosis (negative selection) or restrained by regulatory T (Treg) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref...
December 3, 2015: Nature
Zhiduo Liu, Michael Y Gerner, Nicholas Van Panhuys, Andrew G Levine, Alexander Y Rudensky, Ronald N Germain
FOXP3(+) regulatory T cells (Treg cells) prevent autoimmunity by limiting the effector activity of T cells that have escaped thymic negative selection or peripheral inactivation. Despite the information available about molecular factors mediating the suppressive function of Treg cells, the relevant cellular events in intact tissues remain largely unexplored, and whether Treg cells prevent activation of self-specific T cells or primarily limit damage from such cells has not been determined. Here we use multiplex, quantitative imaging in mice to show that, within secondary lymphoid tissues, highly suppressive Treg cells expressing phosphorylated STAT5 exist in discrete clusters with rare IL-2-positive T cells that are activated by self-antigens...
December 10, 2015: Nature
Ajithkumar Vasanthakumar, Axel Kallies
Foxp3(+) regulatory T (Treg) cells suppress auto-reactive and inflammatory T cells to maintain immune homeostasis. In a recent study, Rudensky and colleagues demonstrate the ability of Treg cells to facilitate tissue repair, a non-canonical Treg cell function accomplished by amphiregulin and mediated by cytokines interleukin (IL)-18 and IL-33.
December 2015: Trends in Immunology
Aaron Arvey, Joris van der Veeken, George Plitas, Stephen S Rich, Patrick Concannon, Alexander Y Rudensky
Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification...
October 28, 2015: ELife
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