- Infectious Diseases
Regulation of host defense and tolerance by Stat transcription factors
PhD (2001), Duke University
My research is devoted to understanding the mechanisms that regulate host defense on one hand and tolerance on the other. Signal transducers and activators of transcription (Stats) are a family latent cytosolic transcription factors activated by cytokins and growth factors that regulate this pivotal balance. Activated Stats impart distinct effect or functions on developing naive CD4+ T cells to tune adaptive immune responses. The activation of Stat4 by interleukin 12 (IL-12) and related cytokines is critically important in the defense against intracellular pathogens through the Stat4-dependent induction of the potent inflammatory cytokine, interferon-y (IFN-y). This pathway is particularly relevant in light of the recent escalation in the incidence of multi-drug resistant forms of tuberculosis, a leading cause of infectious death. In order to better understand the physiologic functions of Stat4 as they pertain to cell-mediated immunity, we have performed microarray analysis to identify genes regulated by IL-12. Among many IL-12 inductible genes, we identified the mitogene- activated protein kinase Tpl2 (aka MAP3K8)as a bonafide Stat4 target gene. Current research is aimed at understanding the contribution(s) of Tpl2and other Stat4 target genes to the regulation of T helper cell development and host immune responses to infectious and autoimmune disease settings.
Gil MP, Ploquin MJ, Watford WT , Lee SH, Kim K, Wang X, Kanno Y, O’Shea JJ, Biron CA. Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function. Blood. 2012 Nov 1;120(18):3718-28.
Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT , Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ. Generation of pathogenic T(H)17 cells in the absence of TGF-ß signalling. Nature. 2010 Oct 21;467(7318):967-71.
Wei L, Vahedi G, Sun HW, Watford WT , Takatori H, Ramos HL, Takahashi H, Liang J, Gutierrez-Cruz G, Zang C, Peng W, O’Shea JJ, Kanno Y. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity. 2010 Jun 25;32(6):840-51.
Durant L, Watford WT , Ramos HL, Laurence A, Vahedi G, Wei L, Takahashi H, Sun HW, Kanno Y, Powrie F, O’Shea JJ. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity. 2010 May 28;32(5):605-15.
Watford WT , Wang CC, Tsatsanis C, Mielke LA, Eliopoulos AG, Daskalakis C, Charles N, Odom S, Rivera J, O’Shea J, Tsichlis PN. Ablation of tumor progression locus 2 promotes a type 2 Th cell response in Ovalbumin-immunized mice. J Immunol. 2010 Jan 1;184(1):105-13.
Mielke LA, Elkins KL, Wei L, Starr R, Tsichlis PN, O’Shea JJ, Watford WT . Tumor progression locus 2 (Map3k8) is critical for host defense against Listeria monocytogenes and IL-1 beta production. J Immunol. 2009 Dec 15;183(12):7984-93.
Brydges SD, Mueller JL, McGeough MD, Pena CA, Misaghi A, Gandhi C, Putnam CD, Boyle DL, Firestein GS, Horner AA, Soroosh P, Watford WT , O’Shea JJ, Kastner DL, Hoffman HM. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity. 2009 Jun 19;30(6):875-87.
O’Shea JJ, Steward-Tharp SM, Laurence A, Watford WT , Wei L, Adamson AS, Fan S. Signal transduction and Th17 cell differentiation. Microbes Infect. 2009 Apr;11(5):599-611.
Charles N, Watford WT , Ramos HL, Hellman L, Oettgen HC, Gomez G, Ryan JJ, O’Shea JJ, Rivera J. Lyn kinase controls basophil GATA-3 transcription factor expression and induction of Th2 cell differentiation. Immunity. 2009 Apr 17;30(4):533-43.
Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, Cui K, Kanno Y, Roh TY, Watford WT , Schones DE, Peng W, Sun HW, Paul WE, O’Shea JJ, Zhao K. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009 Jan