Mark H. Kaplan, PhD
Chair, Department of Microbiology & Immunology
Professor Kaplan received an Honours B.Sc. from the University of Windsor in 1987 (Biology) and a PhD. from Wayne State University in 1992 (Immunology and Microbiology). He did postdoctoral work at the University of Texas Southwestern Medical Center and at the Harvard University School of Public Health. He joined the Faculty in the Indiana University School of Medicine in 1998 as an Assistant Professor of Microbiology and Immunology. In 2005, he moved to the Department of Pediatrics to become the Director of Pediatric Pulmonary Basic Research. In 2008, he was promoted to Professor and in 2014 was honored with the Billie Lou Wood Professorship. In 2017, Dr. Kaplan was named as Associate Director of the HB Wells Center for Pediatric Research.
Professor Kaplan’s work is focused on understanding the function of transcription factors in the development of T helper cell subsets. He has a long standing interest in Signal Transducer and Activator of Transcription or STAT proteins that are activated downstream of cytokines. His more recent work has made great progress towards understanding the development and function of IL-9-secreting T cells in the development of allergic inflammation. His interests lie in understanding how T cell subsets contribute to allergic and autoimmune inflammation.
Professor Kaplan has been on the Editorial Boards of the Journal of Immunology and JAK-STAT and is currently Senior Editor for the new American Association of Immunologists journal ImmunoHorizons. He has served on and chaired numerous study sections for grant application to the National Institutes of Health, and other private and international review panels. He has served on the IUSM Biomedical Research Committee for over ten years and is currently the co-chair. He is also the Director of the NIH-funded T32 Training Program in Immunology and Infectious Diseases.
Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL, Jabeen R, Han L, Nguyen ET, McKinley CD, Tepper RS, Robertson MJ, Perumal NB, Nutt SL and Kaplan MH. (2010) The transcription factor PU.1 is required for the development of IL-9-secreting T cells and allergic inflammation. Nature Immunology. 11:527-534. PMC3136246.
Jabeen R, Goswami R, Awe O, Kulkarni A, Nguyen ET, Attenasio A, Walsh D, Olson MR, Kim MH, Tepper RS, Sun J, Kim CH, Taparowsky EJ, Zhou B and Kaplan MH. (2013). Th9 cell development requires a BATF-regulated transcriptional network. Journal of Clinical Investigation. 123(11):4641–4653. PMC3809790.
Sehra S, Yao W, Nguyen ET, Glosson-Byers NL, Akhtar N, Zhou B, and Kaplan MH. (2015). Th9 cells are required for tissue mast cell accumulation during allergic inflammation. J Allergy Clin Immunol. 136(2):433-440.e1. PMC4530056
Kaplan MH, Hufford MM, Olson, MR. (2015) The Development and in vivo Function of TH9 cells. Nature Reviews Immunol.15:295-307. PMC4445728.
Serezani APM, Bozdogan G, Sehra S, Walsh D, Krishnamurthy P, Potchanant EAS, Nalepa G, Goenka S, Turner MJ, Spandau DF, Kaplan MH. (2017) IL-4 impairs wound healing potential in the skin by repressing fibronectin expression. J. Allergy Clin Immunol. 139(1):142-151.e5. PMC5222746
Olson MR, Ulrich BJ, Hummel SA, Khan I, Meuris B, Cherukuri Y, Dent AL, Janga SC, and Kaplan MH. (2017) Paracrine IL-2 is required for optimal type 2 effector cytokine production. J. Immunol. 198:4352-4359. PMCID:PMC5470780
Ulrich BJ, Verdan FF, McKenzie ANJ, Kaplan MH, and Olson MR. (2017) STAT3 activation impairs the stability of Th9 cells. J. Immunol. 198(6):2302-2309. PMC5340611
Microbiology & Immunology
Wells Center for Pediatric Research 1044 West Walnut St. Room 202
Indianapolis, IN 46202
Titles & Appointments
- Director of Basic Science, Brown Center for Immunotherapy
- Nicole Brown Professor of Immunology
- Professor of Microbiology & Immunology
- Professor of Pediatrics
- Adjunct Professor of Biochemistry & Molecular Biology
The overall focus of my laboratory over the last 16 years has been on understanding the transcriptional regulation of T helper cells as they regulate inflammatory immunity (Figure below). This line of research began when I was a postdoctoral fellow and generated STAT4- and STAT6-deficient mice in Michael Grusby’s laboratory. The early years of my laboratory’s work continued the characterization of STAT4 and STAT6 function, working at multiple levels, from examining gene regulatory mechanisms and chromatin modifications, to defining how factors control cellular function and inflammatory disease in mouse model system, to finally trying to take observations to using human and patient samples to demonstrate the link between basic research and human immune-mediated health and disease.
My laboratory’s multi-level approach, performing hard-core studies on transcription factor-dependent gene regulation, defining transcription factor-mediated changes in cell function in vitro and in vivo, and ultimately showing conservation in human samples and where possible, linkage to human disease, continues to be a strength in our studies.
STAT protein function in T helper cells and allergic inflammation
A large portion of work in the lab focuses on understanding how STAT proteins regulate the development of T helper cell differentiation programs. Over the last 15 years of the grant, we have defined STAT4 target genes during Th1 differentiation, determined mechanisms of STAT4-dependent gene activation including examining chromatin modifying enzymes and DNA methyltransferases, defined in vivo functions of STAT4-dependent responses in inflammatory disease and pathogen immunity. We have characterized STAT4 isoform function in vivo, and have recently demonstrated altered expression of STAT4 isoforms in patients with inflammatory bowel disease. We have defined how STAT4 integrates with other transcription factors that promote the development of Th1 cells. Among downstream targets of STAT4, we have recently characterized Twist1 and Etv5 as downstream effectors of both STAT4 and STAT3-dependent immunity. We are now expanding our studies into an understanding of STAT4 function in myeloid cells during immune-mediated disease.
We identified an unexpected role for STAT3 in Th2 several years ago and recently completed an R03 grant to further explore how the STAT3 signal is integrated in various Th subsets. We identified several interesting aspects of STAT3 signaling in Th2 cells including a balance with activation of other STAT proteins, and the induction of genes that may identify a novel functional subset of Th cells in the skin. These studies are ongoing and further grant applications are planned.
This latter point links to another interest of the laboratory, allergic skin inflammation. Over a decade ago we developed a mouse model transgenic for a constitutively active STAT6 in T cells. These mice are predisposed towards spontaneous allergic inflammation, particularly in the skin. We have characterized the pathogenesis of skin inflammation in this strain focusing in two areas. The first uses this mouse model to test the interactions between the hyperactive Th2 immune response and dysfunction in the barrier function of the skin. The second approach is this area is to define how Th2 cytokines, specifically IL-4, impact keratinocyte gene expression and differentiation. We are using RNA-seq and ChIP-seq approaches to define how the IL-4/STAT6 pathway function in non-immune cells.
IL-9 secreting Th9 cells
Among the most recent subsets of T cells described, Th cells that are primed for production of IL-9 are still very poorly understood. We have made significant progress in understanding the development and function of Th9 cells. We have demonstrated that PU.1 is a major transcription factor in the development of IL-9-secreting T cells, and that PU.1-expressing T cells are important for the development of allergic lung inflammation in several mouse models. This project has focused on PU.1 and over the past ten years we have demonstrated the ability of PU.1 to function as a switch factor, both repressing Th2 development as it increases Th9 development. More recently we have published microarray studies of Th9 cells and found several genes that suggest unique functions of Th9 cells. We are expanding work in this area to examine other PU.1-related ETS factors in the development of Th9 cells, and to examine other transcription factors including BATF and their contribution to IL-9 production and Th9 function.
We are also interested in understanding the biology of IL-9 during allergic inflammation and other types of immune responses. We recently identified TSLP as an important co-factor in promoting IL-9 production from human and mouse cells and are developing further projects to expand from that observation. Among other important questions in this area are defining the relevant IL-9-responding populations during the development of inflammatory disease, and tracking the IL-9-secreting cells in vivo during initiation of inflammation and during allergen challenge. Th9 cells have roles in autoimmunity and tumor immunity that are still largely unexplored.
A final area of interest is allergic disease and we have ongoing studies in several areas. First, I have collaborated with physician-scientists at IU to examine immune and lung function in infants and toddlers with atopic dermatitis. Planned studies focus on testing the ability of food allergen elimination to affect lung function. We are also interested in understanding regulation of the IgE response in vivo, from the standpoint of examining the relative roles of Th2 and Tfh cells in generating low and high affinity IgE antibodies. Finally, we are collaborating with a biochemical engineer at University of Notre Dame who has developed novel reagents for both testing mast cell activation in the context of heterovalent allergens, and also developed reagents that inhibit allergen-stimulated IgE responses. We are collaborating with him to obtain funding to refine the molecular development, and also to perform more in vivo and molecular studies to assess the efficacy of this approach in an allergen model.
American Association for the Advancement of Science
American Association of Immunologists
Desc: IUSM Faculty Mentoring Award
Desc: Billie Lou Wood Endowed Chair