IU Indianapolis ScholarWorks :: Browsing by Author "Olson, Matthew R."

Browsing by Author "Olson, Matthew R."

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The development and in vivo function of T helper 9 cells
(SpringerNature, 2015-05) Kaplan, Mark H.; Hufford, Matthew M.; Olson, Matthew R.; Department of Pediatrics, IU School of Medicine
The specialized cytokine secretion profiles of T helper (TH) cells are the basis for a focused and efficient immune response. On the 20th anniversary of the first descriptions of cytokine signals that act to differentiate interleukin-9 (IL-9)-secreting T cells, this review focuses on the extracellular signals and transcription factors that promote the development of what we now term TH9 cells, which are characterized by the production of this cytokine. We summarize our current understanding of the contribution of TH9 cells to both effective immunity and immunopathological disease and propose that TH9 cells could be targeted for the treatment of allergic and autoimmune disease.
Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation
(Cell Press, 2017-03-16) Cheung, Ka Lung; Zhang, Fan; Jaganathan, Anbalagan; Sharma, Rajal; Zhang, Qiang; Konuma, Tsuyoshi; Shen, Tong; Lee, June-Yong; Ren, Chunyan; Chen, Chih-Hung; Lu, Geming; Olson, Matthew R.; Zhang, Weijia; Kaplan, Mark H.; Littman, Dan R.; Walsh, Martin J.; Xiong, Huabao; Zeng, Lei; Zhou, Ming-Ming; Pediatrics, School of Medicine
The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T-helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclinT1/Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity., , Cheung et al. uncover both separate and interdependent Brd2 and Brd4 genomic functions in potentiating the genetic program required for Th17 cell development and adaptive immunity. Brd2 interacts with transcription factor Stat3 and chromatin insulator CTCF/cohesin complex to support enhancer assembly, whereas Brd4 temporally controls RNA PolII for transcription elongation.
Effector T Helper Cell Subsets in Inflammatory Bowel Diseases
(Frontiers Media, 2018-06-01) Imam, Tanbeena; Park, Sungtae; Kaplan, Mark H.; Olson, Matthew R.; Pediatrics, School of Medicine
The gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4+ T cells are key in mediating the host protective and homeostatic responses. Yet, CD4+ T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4+ T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.
The ETS family transcription factors Etv5 and PU.1 function in parallel to promote Th9 cell development
(American Association of Immunologists, 2016-09-15) Koh, Byunghee; Hufford, Matthew M; Pham, Duy; Olson, Matthew R.; Wu, Tong; Jabeen, Rukhsana; Sun, Xin; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
The IL-9-secreting Th9 subset of CD4 T helper cells develop in response to an environment containing IL-4 and TGFβ, promoting allergic disease, autoimmunity, and resistance to pathogens. We previously identified a requirement for the ETS family transcription factor PU.1 in Th9 development. In this report we demonstrate that the ETS transcription factor ETV5 promotes IL-9 production in Th9 cells by binding and recruiting histone acetyltransferases to the Il9 locus at sites distinct from PU.1. In cells that are deficient in both PU.1 and ETV5 there is lower IL-9 production than in cells lacking either factor alone. In vivo loss of PU.1 and ETV5 in T cells results in distinct affects on allergic inflammation in the lung, suggesting that these factors function in parallel. Together, these data define a role for ETV5 in Th9 development and extend the paradigm of related transcription factors having complementary functions during differentiation.
Granzyme A–producing T helper cells are critical for acute graft-versus-host disease
(American Society for Clinical Investigation, 2020-08-18) Park, Sungtae; Griesenauer, Brad; Jiang, Hua; Adom, Djamilatou; Mehrpouya-Bahrami, Pegah; Chakravorty, Srishti; Kazemian, Majid; Imam, Tanbeena; Srivastava, Rajneesh; Hayes, Tristan A.; Pardo, Julian; Janga, Sarath Chandra; Paczesny, Sophie; Kaplan, Mark H.; Olson, Matthew R.; Microbiology and Immunology, School of Medicine
Acute graft-versus-host disease (aGVHD) can occur after hematopoietic cell transplant in patients undergoing treatment for hematological malignancies or inborn errors. Although CD4+ T helper (Th) cells play a major role in aGVHD, the mechanisms by which they contribute, particularly within the intestines, have remained elusive. We have identified a potentially novel subset of Th cells that accumulated in the intestines and produced the serine protease granzyme A (GrA). GrA+ Th cells were distinct from other Th lineages and exhibited a noncytolytic phenotype. In vitro, GrA+ Th cells differentiated in the presence of IL-4, IL-6, and IL-21 and were transcriptionally unique from cells cultured with either IL-4 or the IL-6/IL-21 combination alone. In vivo, both STAT3 and STAT6 were required for GrA+ Th cell differentiation and played roles in maintenance of the lineage identity. Importantly, GrA+ Th cells promoted aGVHD-associated morbidity and mortality and contributed to crypt destruction within intestines but were not required for the beneficial graft-versus-leukemia effect. Our data indicate that GrA+ Th cells represent a distinct Th subset and are critical mediators of aGVHD.
IL-1β promotes IL-9-producing Th cell differentiation in IL-2-limiting conditions through the inhibition of BCL6
(Frontiers Media, 2022-11-01) Canaria, D. Alejandro; Clare, Maia G.; Yan, Bingyu; Campbell, Charlotte B.; Ismaio, Zachariah A.; Anderson, Nicole L.; Park, Sungtae; Dent, Alexander L.; Kazemian, Majid; Olson, Matthew R.; Microbiology and Immunology, School of Medicine
IL-9-producing CD4+ T helper cells, termed Th9 cells, differentiate from naïve precursor cells in response to a combination of cytokine and cell surface receptor signals that are elevated in inflamed tissues. After differentiation, Th9 cells accumulate in these tissues where they exacerbate allergic and intestinal disease or enhance anti-parasite and anti-tumor immunity. Previous work indicates that the differentiation of Th9 cells requires the inflammatory cytokines IL-4 and TGF-β and is also dependent of the T cell growth factor IL-2. While the roles of IL-4 and TGF-β-mediated signaling are relatively well understood, how IL-2 signaling contributes to Th9 cell differentiation outside of directly inducing the Il9 locus remains less clear. We show here that murine Th9 cells that differentiate in IL-2-limiting conditions exhibit reduced IL-9 production, diminished NF-kB activation and a reduced NF-kB-associated transcriptional signature, suggesting that IL-2 signaling is required for optimal NF-kB activation in Th9 cells. Interestingly, both IL-9 production and the NF-kB transcriptional signature could be rescued by addition of the NF-kB-activating cytokine IL-1β to IL-2-limiting cultures. IL-1β was unique among NF-kB-activating factors in its ability to rescue Th9 differentiation as IL-2 deprived Th9 cells selectively induced IL-1R expression and IL-1β/IL-1R1 signaling enhanced the sensitivity of Th9 cells to limiting amounts of IL-2 by suppressing expression of the Th9 inhibitory factor BCL6. These data shed new light on the intertwined nature of IL-2 and NF-kB signaling pathways in differentiating Th cells and elucidate the potential mechanisms that promote Th9 inflammatory function in IL-2-limiting conditions.
Paracrine IL-2 Is Required for Optimal Type 2 Effector Cytokine Production
(American Association of Immunologists, 2017-06-01) Olson, Matthew R.; Ulrich, Benjamin J.; Hummel, Sarah A.; Khan, Ibrahim; Meuris, Brice; Cherukur, Yesesri; Dent, Alexander L.; Janga, Sarath Chandra; Kaplan, Mark H.; Pediatrics, School of Medicine
IL-2 is a pleiotropic cytokine that promotes the differentiation of Th cell subsets, including Th1, Th2, and Th9 cells, but it impairs the development of Th17 and T follicular helper cells. Although IL-2 is produced by all polarized Th subsets to some level, how it impacts cytokine production when effector T cells are restimulated is unknown. We show in this article that Golgi transport inhibitors (GTIs) blocked IL-9 production. Mechanistically, GTIs blocked secretion of IL-2 that normally feeds back in a paracrine manner to promote STAT5 activation and IL-9 production. IL-2 feedback had no effect on Th1- or Th17-signature cytokine production, but it promoted Th2- and Th9-associated cytokine expression. These data suggest that the use of GTIs results in an underestimation of the presence of type 2 cytokine-secreting cells and highlight IL-2 as a critical component in optimal cytokine production by Th2 and Th9 cells in vitro and in vivo.
Phenotyping acute and chronic atopic dermatitis-like lesions in Stat6VT mice identifies a role for IL-33 in disease pathogenesis
(Springer, 2018-04) DaSilva-Arnold, Sonia C.; Thyagarajan, Anita; Seymour, Leroy J.; Yi, Qiaofang; Bradish, Joshua R.; Al-Hassani, Mohammed; Zhou, Hongming; Perdue, Nikolajs J.; Nemmeth, Val; Krbanjevic, Aleksandar; Serezani, Ana P. M.; Olson, Matthew R.; Spandau, Dan F.; Travers, Jeffrey B.; Kaplan, Mark H.; Turner, Matthew J.; Dermatology, School of Medicine
The Stat6VT mouse model of atopic dermatitis (AD) is induced by T-cell-specific expression of a constitutively active form of the protein signal transducer and activator of transcription 6 (STAT6). Although AD-like lesions are known to develop in Stat6VT mice, this study was designed to determine if these mice develop acute and chronic phases of disease similar to humans. To address this, AD-like lesions from Stat6VT mice were harvested at two different timepoints relative to their onset. Lesions harvested within 1 week after development were defined as acute lesions, and those present for 1 month or more were defined as chronic lesions. Acute and chronic AD-like lesions from Stat6VT mice exhibited histologic findings and cytokine expression patterns similar to acute and chronic AD lesions in humans. Further analysis revealed increased levels of interleukin (IL)-33 transcripts in AD-like lesions compared to Stat6VT nonlesional and wild-type skin controls. Immunofluorescence also revealed increased numbers of IL-33+ keratinocytes in Stat6VT lesional skin and localized IL-33+ keratinocytes to a keratin 5+ subset. Furthermore, AD-like disease was more severe in IL-33-deficient Stat6VT mice compared to IL-33-sufficient Stat6VT mice. These studies suggest that Stat6VT mice can serve as a model of acute and chronic AD and that IL-33 may attenuate inflammation in this system.
STAT3 activation impairs the stability of Th9 cells
(American Association of Immunologists, 2017-03-15) Ulrich, Benjamin J.; Verdan, Felipe Fortino; McKenzie, Andrew N.J.; Kaplan, Mark H.; Olson, Matthew R.; Microbiology and Immunology, School of Medicine
Th9 cells regulate multiple immune responses including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. Despite ongoing research into Th9 development and function, little is known about the stability of the Th9 phenotype. In this report we demonstrate that IL-9 production is progressively lost in Th9 cultures over several rounds of differentiation. The loss of IL-9 is not due to an outgrowth of cells that do not secrete IL-9, as purified IL-9 secretors demonstrate the same loss of IL-9 in subsequent rounds of differentiation. The loss of IL-9 production correlates with increases in phospho-STAT3 levels within the cell, and the production of IL-10. STAT3-deficient Th9 cells have increased IL-9 production that is maintained for longer in culture than IL-9 in control cultures. IL-10 is responsible for STAT3 activation during the first round of differentiation, and contributes to instability in subsequent rounds of culture. Together, our results indicate that environmental cues dictate the instability of the Th9 phenotype, and suggest approaches to enhance Th9 activity in beneficial immune responses.
STAT3 Impairs STAT5 Activation in the Development of IL-9-Secreting T Cells
(The American Association of Immunologists, Inc., 2016-04-15) Olson, Matthew R.; Verdan, Felipe Fortino; Hufford, Matthew M.; Dent, Alexander L.; Kaplan, Mark H.; Pediatrics, School of Medicine
Th cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9-secreting T cells develop in response to the combination of IL-4 and TGF-β, although they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, although whether this paradigm exists in other Th subsets is not clear. In this paper, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9-secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3 and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild-type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function.

Browsing by Author "Olson, Matthew R."

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