Acute exercise leads to regulation of Telomere-Associated genes and MicroRNA expression in immune Cells
- Chilton, Warrick, Marques, Francine, West, Jenny, Kannourakis, George, Berzins, Stuart, O'Brien, Brendan, Charchar, Fadi
- Authors: Chilton, Warrick , Marques, Francine , West, Jenny , Kannourakis, George , Berzins, Stuart , O'Brien, Brendan , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: PloS One Vol. 9, no. 4 (2014), p. e92088
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- Description: Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health. Funding NHMRC
- Authors: Chilton, Warrick , Marques, Francine , West, Jenny , Kannourakis, George , Berzins, Stuart , O'Brien, Brendan , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: PloS One Vol. 9, no. 4 (2014), p. e92088
- Full Text:
- Reviewed:
- Description: Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health. Funding NHMRC
Altered populations of unconventional T Cell lineages in patients with Langerhans Cell Histiocytosis
- Mitchell, Jenée, Kvedaraite, Egle, von Bahr Greenwood, Tatiana, Henter, Jan-Inge, Pellicci, Daniel, Berzins, Stuart, Kannourakis, George
- Authors: Mitchell, Jenée , Kvedaraite, Egle , von Bahr Greenwood, Tatiana , Henter, Jan-Inge , Pellicci, Daniel , Berzins, Stuart , Kannourakis, George
- Date: 2018
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 8, no. 1 (2018), p. 1-13
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- Description: Langerhans cell histiocytosis (LCH) lesions are defined by the presence of CD1a+/CD207+ myeloid cells, but many other immune cells are present including unconventional T cells, which have powerful immunoregulatory functions. Unconventional T cell lineages include mucosal-associated invariant T (MAIT) cells, type I natural killer T (NKT) cells and gamma-delta (γδ) T cells, which are associated with many inflammatory conditions, although their importance has not been studied in LCH. We characterized their phenotype and function in blood and lesions from patients with LCH, and identified a deficiency in MAIT cell frequency and abnormalities in the subset distributions of γδ T cells and NKT cells. Such abnormalities are associated with immune dysregulation in other disease settings and are therefore potentially important in LCH. Our study is the first to recognize alterations to MAIT cell proportions in patients with LCH. This finding along with other abnormalities identified amongst unconventional T cells could potentially influence the onset and progression of LCH, thereby highlighting potential targets for new immune based therapies.
Altered populations of unconventional T Cell lineages in patients with Langerhans Cell Histiocytosis
- Authors: Mitchell, Jenée , Kvedaraite, Egle , von Bahr Greenwood, Tatiana , Henter, Jan-Inge , Pellicci, Daniel , Berzins, Stuart , Kannourakis, George
- Date: 2018
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 8, no. 1 (2018), p. 1-13
- Full Text:
- Reviewed:
- Description: Langerhans cell histiocytosis (LCH) lesions are defined by the presence of CD1a+/CD207+ myeloid cells, but many other immune cells are present including unconventional T cells, which have powerful immunoregulatory functions. Unconventional T cell lineages include mucosal-associated invariant T (MAIT) cells, type I natural killer T (NKT) cells and gamma-delta (γδ) T cells, which are associated with many inflammatory conditions, although their importance has not been studied in LCH. We characterized their phenotype and function in blood and lesions from patients with LCH, and identified a deficiency in MAIT cell frequency and abnormalities in the subset distributions of γδ T cells and NKT cells. Such abnormalities are associated with immune dysregulation in other disease settings and are therefore potentially important in LCH. Our study is the first to recognize alterations to MAIT cell proportions in patients with LCH. This finding along with other abnormalities identified amongst unconventional T cells could potentially influence the onset and progression of LCH, thereby highlighting potential targets for new immune based therapies.
Divergent molecular networks program functionally distinct CD8+skin-resident memory T cells
- Park, Simone, Christo, Susan, Wells, Alexandria, Gandolfo, Luke, Zaid, Ali, Alexandre, Yannick, Burn, Thomas, Schröder, Jan, Collins, Nicholas, Han, Seong-Ji, Guillaume, Stephane, Evrard, Maximilien, Castellucci, Clara, Davies, Brooke, Osman, Maleika, Obers, Andreas, McDonald, Keely, Wang, Huimeng, Mueller, Scott, Kannourakis, George, Berzins, Stuart, Mielke, Lisa, Carbone, Francis, Kallies, Axel, Speed, Terence, Belkaid, Yasmine, MacKay, Laura
- Authors: Park, Simone , Christo, Susan , Wells, Alexandria , Gandolfo, Luke , Zaid, Ali , Alexandre, Yannick , Burn, Thomas , Schröder, Jan , Collins, Nicholas , Han, Seong-Ji , Guillaume, Stephane , Evrard, Maximilien , Castellucci, Clara , Davies, Brooke , Osman, Maleika , Obers, Andreas , McDonald, Keely , Wang, Huimeng , Mueller, Scott , Kannourakis, George , Berzins, Stuart , Mielke, Lisa , Carbone, Francis , Kallies, Axel , Speed, Terence , Belkaid, Yasmine , MacKay, Laura
- Date: 2023
- Type: Text , Journal article
- Relation: Science Vol. 382, no. 6674 (2023), p. 1073-1079
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- Description: Skin-resident CD8+T cells include distinct interferon-g-producing [tissue-resident memory T type 1 (TRM1)] and interleukin-17 (IL-17)-producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in the skin. TRM1 cells depend on a T-bet-Hobit-IL-15 axis, whereas TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to TRM17 cell commitment. Accordingly, by targeting this pathway, skin TRM17 cells can be ablated without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity. © 2023 American Association for the Advancement of Science. All rights reserved.
Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population
- Coquet, Jonathan, Chakravarti, Sumone, Kyparissoudis, Konstantinos, McNab, Finlay, Pitt, Lauren, McKenzie, Brent, Berzins, Stuart, Smyth, Mark, Godfrey, Dale
- Authors: Coquet, Jonathan , Chakravarti, Sumone , Kyparissoudis, Konstantinos , McNab, Finlay , Pitt, Lauren , McKenzie, Brent , Berzins, Stuart , Smyth, Mark , Godfrey, Dale
- Date: 2008
- Type: Text , Journal article
- Relation: Proceedings of the National Academy of Sciences of the United States of America Vol. 105, no. 32 (August 2008 2008), p. 11287-11292
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- Description: NKT cell subsets can be divided based on CD4 and NK1.1 expression and tissue of origin, but the developmental and functional relationships between the different subsets still are poorly understood. A comprehensive study of 19 cytokines across different NKT cell subsets revealed that no two NKT subpopulations exhibited the same cytokine profile, and, remarkably, the amounts of each cytokine produced varied by up to 100-fold or more among subsets. This study also revealed the existence of a population of CD4-NK1.1 - NKT cells that produce high levels of the proinflammatory cytokine IL-17 within 2-3 h of activation. On intrathymic transfer these cells develop into mature CD4-NK1.1+ but not into CD4 +NK1.1+ NKT cells, indicating that CD4-NK1. 1- NKT cells include an IL-17-producing subpopulation, and also mark the elusive branch point for CD4+ and CD4- NKT cell sublineages.
- Description: C1
- Authors: Coquet, Jonathan , Chakravarti, Sumone , Kyparissoudis, Konstantinos , McNab, Finlay , Pitt, Lauren , McKenzie, Brent , Berzins, Stuart , Smyth, Mark , Godfrey, Dale
- Date: 2008
- Type: Text , Journal article
- Relation: Proceedings of the National Academy of Sciences of the United States of America Vol. 105, no. 32 (August 2008 2008), p. 11287-11292
- Full Text:
- Reviewed:
- Description: NKT cell subsets can be divided based on CD4 and NK1.1 expression and tissue of origin, but the developmental and functional relationships between the different subsets still are poorly understood. A comprehensive study of 19 cytokines across different NKT cell subsets revealed that no two NKT subpopulations exhibited the same cytokine profile, and, remarkably, the amounts of each cytokine produced varied by up to 100-fold or more among subsets. This study also revealed the existence of a population of CD4-NK1.1 - NKT cells that produce high levels of the proinflammatory cytokine IL-17 within 2-3 h of activation. On intrathymic transfer these cells develop into mature CD4-NK1.1+ but not into CD4 +NK1.1+ NKT cells, indicating that CD4-NK1. 1- NKT cells include an IL-17-producing subpopulation, and also mark the elusive branch point for CD4+ and CD4- NKT cell sublineages.
- Description: C1
Modulation of TCR signalling components occurs prior to positive selection and lineage commitment in iNKT cells
- Dinh, Xuyen, Stanley, Dragana, Smith, Letitia, Moreau, Morgane, Berzins, Stuart
- Authors: Dinh, Xuyen , Stanley, Dragana , Smith, Letitia , Moreau, Morgane , Berzins, Stuart
- Date: 2021
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 11, no. 1 (2021), p.
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- Description: iNKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. Their unique functional characteristics are induced by a transcriptional program initiated by positive selection mediated by CD1d expressed by CD4+CD8+ (double positive, DP) thymocytes. Here, using a novel Vα14 TCR transgenic strain bearing greatly expanded numbers of CD24hiCD44loNKT cells, we examined transcriptional events in four immature thymic iNKT cell subsets. A transcriptional regulatory network approach identified transcriptional changes in proximal components of the TCR signalling cascade in DP NKT cells. Subsequently, positive and negative selection, and lineage commitment, occurred at the transition from DP NKT to CD4 NKT. Thus, this study introduces previously unrecognised steps in early NKT cell development, and separates the events associated with modulation of the T cell signalling cascade prior to changes associated with positive selection and lineage commitment. © 2021, The Author(s). **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Stuart Berzins” is provided in this record**
- Authors: Dinh, Xuyen , Stanley, Dragana , Smith, Letitia , Moreau, Morgane , Berzins, Stuart
- Date: 2021
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 11, no. 1 (2021), p.
- Full Text:
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- Description: iNKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. Their unique functional characteristics are induced by a transcriptional program initiated by positive selection mediated by CD1d expressed by CD4+CD8+ (double positive, DP) thymocytes. Here, using a novel Vα14 TCR transgenic strain bearing greatly expanded numbers of CD24hiCD44loNKT cells, we examined transcriptional events in four immature thymic iNKT cell subsets. A transcriptional regulatory network approach identified transcriptional changes in proximal components of the TCR signalling cascade in DP NKT cells. Subsequently, positive and negative selection, and lineage commitment, occurred at the transition from DP NKT to CD4 NKT. Thus, this study introduces previously unrecognised steps in early NKT cell development, and separates the events associated with modulation of the T cell signalling cascade prior to changes associated with positive selection and lineage commitment. © 2021, The Author(s). **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Stuart Berzins” is provided in this record**
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