Browsing by Author "Mehrpouya-Bahrami, Pegah"

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    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.
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    STAT4 is expressed in neutrophils and promotes antimicrobial immunity
    (American Society for Clinical Investigation, 2021-07-22) Mehrpouya-Bahrami, Pegah; Moriarty, Alina K.; De Melo, Paulo; Keeter, W. Coles; Alakhras, Nada S.; Nelson, Andrew S.; Hoover, Madeline; Barrios, Maria S.; Nadler, Jerry L.; Serezani, C. Henrique; Kaplan, Mark H.; Galkina, Elena V.; Microbiology and Immunology, School of Medicine
    Signal transducer and activator of transcription 4 (STAT4) is expressed in hematopoietic cells and plays a key role in the differentiation of T helper 1 cells. Although STAT4 is required for immunity to intracellular pathogens, the T cell-independent protective mechanisms of STAT4 are not clearly defined. In this report, we demonstrate that STAT4-deficient mice were acutely sensitive to methicillin-resistant Staphylococcus aureus (MRSA) infection. We show that STAT4 was expressed in neutrophils and activated by IL-12 via a JAK2-dependent pathway. We demonstrate that STAT4 was required for multiple neutrophil functions, including IL-12-induced ROS production, chemotaxis, and production of the neutrophil extracellular traps. Importantly, myeloid-specific and neutrophil-specific deletion of STAT4 resulted in enhanced susceptibility to MRSA, demonstrating the key role of STAT4 in the in vivo function of these cells. Thus, these studies identify STAT4 as an essential regulator of neutrophil functions and a component of innate immune responses in vivo.