Calvin B. Williams, MD, PhD
Professor, Pediatrics and Microbiology & Immunology; Associate Dean of Research; Associate Director, Medical Scientist Training Program; Chief Scientific Officer, Children's Wisconsin Research Institute; Chief, Pediatric Rheumatology; Vice Chair, Research, Pediatrics
- Chief Scientific Officer, Children's Research Institute
- Professor of Pediatrics, Microbiology and Immunology
- Section Chief, Pediatric Rheumatology
The broad, long-term objective of research in my laboratory is to establish the mechanisms that promote T cell development in the thymus and maintain T cell tolerance in the periphery. We place special emphasis on role of Foxp3 regulatory T (Treg) cells, and have developed a number of mouse models that are widely used to study Treg cell function. This body of work has contributed to our understanding of T cell receptor antagonism as potent mechanism of peripheral tolerance (1), the mechanisms of Treg cell-mediated suppression in models of inflammatory autoimmune disease (2), the role of Foxp3 in Treg cell development (3), and the identification of “induced” Treg (iTreg) cells as an essential regulatory subset required for mucosal tolerance (4). Current work is focused on discovering the mechanisms that control the inducible components of mucosal tolerance, including the iTreg-Th17 cell axis (Figure 1).
Figure 1. Model of Treg cell development. The nTreg cell population (green) develops as a distinct lineage in the thymus. In the periphery, TGF-b1 induces Tconv cells to become iTreg cells (red) or Th17 cells (purple). The peripheral Treg (pTreg) cell pool is therefore comprised of both iTreg and nTreg cells. IL-6 promotes production of Th17 cells while blocking iTreg cell formation. Smad3 promotes Foxp3 expression and stability. In some circumstances, iTreg cells are unstable and lose Foxp3 expression (ex-Foxp3+ iTreg or “ex-iTreg” cells, pink). These ex-iTreg cells may become Th1 (blue) or Th17 cells, or reacquire Foxp3 and cycle back into the iTreg pool. IL-10 produced by iTreg cells functions in an autocrine feedback loop to promote iTreg cell transcriptional and phenotypic stability. The activation of ex-iTreg cells and their migration from the mesenteric lymph nodes to the intestinal mucosa is also specifically prevented by iTreg cell produced IL-10. In Current work in the lab is divided into three Aims. In Aim 1, we will determine how the iTreg cell niche is created and maintained. In Aim 2 we will examine the fate of ex-iTreg cells, and in Aim 3 we will show that iTreg cell produced IL-10 has both shared and unique roles. in gastrointestinal tolerance.
(Zheng Y, Zhu W, Haribhai D, Williams CB, Aster RH, Wen R, Wang D.) J Immunol. 2019 Aug 30.
(Owen DL, Mahmud SA, Sjaastad LE, Williams JB, Spanier JA, Simeonov DR, Ruscher R, Huang W, Proekt I, Miller CN, Hekim C, Jeschke JC, Aggarwal P, Broeckel U, LaRue RS, Henzler CM, Alegre ML, Anderson MS, August A, Marson A, Zheng Y, Williams CB, Farrar MA.) Nat Immunol. 2019 02;20(2):195-205.
(Naumova EN, Yassai MB, Demos W, Reed E, Unruh M, Haribhai D, Williams CB, Naumov YN, Gorski J.) Front Immunol. 2019;10:1717.
Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease.
(Lovell DJ, Johnson AL, Huang B, Gottlieb BS, Morris PW, Kimura Y, Onel K, Li SC, Grom AA, Taylor J, Brunner HI, Huggins JL, Nocton JJ, Haines KA, Edelheit BS, Shishov M, Jung LK, Williams CB, Tesher MS, Costanzo DM, Zemel LS, Dare JA, Passo MH, Ede KC, Olson JC, Cassidy EA, Griffin TA, Wagner-Weiner L, Weiss JE, Vogler LB, Rouster-Stevens KA, Beukelman T, Cron RQ, Kietz D, Schikler K, Schmidt KM, Mehta J, Wahezi DM, Ting TV, Verbsky JW, Eberhard BA, Spalding S, Chen C, Giannini EH.) Arthritis Rheumatol. 2018 09;70(9):1508-1518.
(Jeschke JC, Mayne CG, Ziegelbauer J, DeCiantis CL, Singh S, Kumar SN, Suchi M, Iwakura Y, Drobyski WR, Salzman NH, Williams CB.) Mucosal Immunol. 2018 07;11(4):1127-1137.
(Luo X, Chen J, Schroeder JA, Allen KP, Baumgartner CK, Malarkannan S, Hu J, Williams CB, Shi Q.) Front Immunol. 2018;9:1950.
(Haribhai D, Luo X, Chen J, Jia S, Shi L, Schroeder JA, Weiler H, Aster RH, Hessner MJ, Hu J, Williams CB, Shi Q.) Blood Adv. 2016 Dec 13;1(2):139-151.
(Belle L, Agle K, Zhou V, Yin-Yuan C, Komorowski R, Eastwood D, Logan B, Sun J, Ghilardi N, Cua D, Williams CB, Gaignage M, Marillier R, van Snick J, Drobyski WR.) Blood. 2016 10 20;128(16):2068-2082.
(Zhou V, Agle K, Chen X, Beres A, Komorowski R, Belle L, Taylor C, Zhu F, Haribhai D, Williams CB, Verbsky J, Blumenschein W, Sadekova S, Bowman E, Ballantyne C, Weaver C, Serody DA, Vincent B, Serody J, Cua DJ, Drobyski WR.) J Clin Invest. 2016 09 01;126(9):3541-55.
(Jeschke JC, Williams CB.) J Leukoc Biol. 2016 07;100(1):1-3.
(Haribhai D, Ziegelbauer J, Jia S, Upchurch K, Yan K, Schmitt EG, Salzman NH, Simpson P, Hessner MJ, Chatila TA, Williams CB.) J Immunol. 2016 Apr 15;196(8):3305-17.
(Haribhai D, Chatila TA, Williams CB.) Methods Mol Biol. 2016;1422:197-211.