Shawn A. Mahmud


     Year Entered: 2008

     Degrees Received:
     St. Olaf College
     Biology major
     B.A., 2001

     Honors and Awards:   
-Ruth L. Kirschstein NRSA Individual Predoctoral MD/PhD Fellowship
     (National Institute of Diabetes and Digestive and Kidney Diseases),
     -Immunology Training Grant (T32), 2010-2012
     -American Society of Hematology Annual Meeting Travel Award, 2007
     -Microbiology, Immunology, and Cancer Biology Graduate Program
     Block Fellowship, 2007
     -Crohn’s and Colitis Foundation of America Student Research
     Fellowship Award, 2007
Thesis Advisor:  Michael Farrar, Ph.D.        -American Society of Hematology Annual Meeting Travel Award, 2006

Thesis Research: CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) develop in the thymus and are indispensible for the prevention of systemic autoimmunity by restraining self-reactive T lymphocytes. The mechanism by which developing thymocytes are diverted to the Treg lineage remains unclear, but involves signaling originating from TCR/CD28 and the common gamma chain-dependent cytokine receptor, IL2Rbeta. Signaling through IL2Rbeta activates STAT5 to undergo nuclear translocation where it drives expression of foxp3, the master regulator of the Treg lineage. Transgenic mice expressing constitutively active STAT5 (STAT5b-CA) have a markedly larger Treg population, while STAT5-/- animals show a pronounced deficit. To elucidate the role of STAT5 in driving foxp3 expression, I will utilize BAC recombineering to generate Foxp3-BAC reporter mice with mutated STAT5 binding sites in the promoter and first intron of foxp3, which we predict will negatively regulate Treg development. I will also utilize chromatin immunoprecipitation (ChIP) and bisulfite sequencing techniques to clarify the role of STAT5 in recruiting chromatin-remodeling enzymes to the foxp3 locus which positively regulate its transcription. 

By augmenting our understanding of cytokine signaling in the transcriptional control of Treg development, these studies may ultimately contribute to the generation of novel therapeutics for treating autoimmunity or other chronic inflammatory disorders.

Publications (pubmed):

Vang KB, Yang J, Mahmud SA, Burchill MA, Vegoe AL, Farrar MA.  IL-2, -7, and -15, but Not Thymic Stromal Lymphopoeitin, Redundantly Govern CD4+Foxp3+ Regulatory T Cell Development.  J Immunol 2008 181: 3285-3290.

Publications Prior to Entering MD/PhD Program:

Wang JG, Mahmud SA, Bitterman PB, Huo Y, Slungaard A. Histone deacetylase inhibitors suppress TF-kappaB-dependent agonist-driven tissue factor expression in endothelial cells and monocytes.  J Biol Chem. 2007;282:28408-28418.

Kowalska MA, Mahmud SA, Lambert MP, Poncz M, Slungaard A. Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge.  Blood. 2007;110:1903-1905.

Wang JG, Mahmud SA, Ngugen J, Slungaard A. Thiocyanate-Dependent Induction of Endothelial Cell Adhesion Molecule Expression by Phagocyte Peroxidases. A Novel HOSCN-Specific Oxidant Mechanism to Amplify Inflammation. J Immunol. 2006;177: 8714-8722.

Wang JG*, Mahmud SA*, Thompson JA, Geng JG, Key NS, Slungaard A.  The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: a potential mechanism for thrombosis in eosinophilic inflammatory states.  Blood 2006;107: 558-565.  (*Authors contributed equally to this manuscript)