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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...
September 5, 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...
2015: ELife
Georg Gasteiger, Xiying Fan, Stanislav Dikiy, Sue Y Lee, Alexander Y Rudensky
Innate lymphoid cells (ILCs) contribute to barrier immunity, tissue homeostasis, and immune regulation at various anatomical sites throughout the body. How ILCs maintain their presence in lymphoid and peripheral tissues thus far has been unclear. We found that in the lymphoid and nonlymphoid organs of adult mice, ILCs are tissue-resident cells that were maintained and expanded locally under physiologic conditions, upon systemic perturbation of immune homeostasis and during acute helminth infection. However, at later time points after infection, cells from hematogenous sources helped to partially replenish the pool of resident ILCs...
November 20, 2015: Science
Alison M Paterson, Scott B Lovitch, Peter T Sage, Vikram R Juneja, Youjin Lee, Justin D Trombley, Carolina V Arancibia-Cárcamo, Raymond A Sobel, Alexander Y Rudensky, Vijay K Kuchroo, Gordon J Freeman, Arlene H Sharpe
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of T cell responses. Germline Ctla4 deficiency is lethal, making investigation of the function of CTLA-4 on mature T cells challenging. To elucidate the function of CTLA-4 on mature T cells, we have conditionally ablated Ctla4 in adult mice. We show that, in contrast to germline knockout mice, deletion of Ctla4 during adulthood does not precipitate systemic autoimmunity, but surprisingly confers protection from experimental autoimmune encephalomyelitis (EAE) and does not lead to increased resistance to MC38 tumors...
September 21, 2015: Journal of Experimental Medicine
Nicholas Arpaia, Jesse A Green, Bruno Moltedo, Aaron Arvey, Saskia Hemmers, Shaopeng Yuan, Piper M Treuting, Alexander Y Rudensky
Regulatory T (Treg) cells suppress immune responses to a broad range of non-microbial and microbial antigens and indirectly limit immune inflammation-inflicted tissue damage by employing multiple mechanisms of suppression. Here, we demonstrate that selective Treg cell deficiency in amphiregulin leads to severe acute lung damage and decreased blood oxygen concentration during influenza virus infection without any measureable alterations in Treg cell suppressor function, antiviral immune responses, or viral load...
August 27, 2015: Cell
Li-Fan Lu, Georg Gasteiger, I-Shing Yu, Ashutosh Chaudhry, Jing-Ping Hsin, Yuheng Lu, Paula D Bos, Ling-Li Lin, Carolyn L Zawislak, Sunglim Cho, Joseph C Sun, Christina S Leslie, Shu-Wha Lin, Alexander Y Rudensky
MicroRNA (miRNA)-dependent regulation of gene expression confers robustness to cellular phenotypes and controls responses to extracellular stimuli. Although a single miRNA can regulate expression of hundreds of target genes, it is unclear whether any of its distinct biological functions can be due to the regulation of a single target. To explore in vivo the function of a single miRNA-mRNA interaction, we mutated the 3' UTR of a major miR-155 target (SOCS1) to specifically disrupt its regulation by miR-155. We found that under physiologic conditions and during autoimmune inflammation or viral infection, some immunological functions of miR-155 were fully or largely attributable to the regulation of SOCS1, whereas others could be accounted only partially or not at all by this interaction...
July 21, 2015: Immunity
Catherine Konopacki, George Plitas, Alexander Rudensky
No abstract text is available yet for this article.
July 2015: Nature Biotechnology
Yongqiang Feng, Alexander Y Rudensky
No abstract text is available yet for this article.
July 2015: Nature Immunology
Saskia Hemmers, Alexander Y Rudensky
Circadian rhythms regulate many aspects of physiology, ranging from sleep-wake cycles and metabolic parameters to susceptibility to infection. The molecular clock, with transcription factor BMAL1 at its core, controls both central and cell-intrinsic circadian rhythms. Using a circadian reporter, we observed dynamic regulation of clock activity in lymphocytes. However, its disruption upon conditional Bmal1 ablation did not alter T- or B-cell differentiation or function. Although the magnitude of interleukin 2 (IL-2) production was affected by the time of bacterial infection, it was independent of cell-intrinsic expression of BMAL1...
June 9, 2015: Cell Reports
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