Gender	Female
E-mail	k.alexandropoulos@mssm.edu
Education and Training	Ph.D., City University of New York (CUNY)
	Postdoctoral, Rockefeller University
	Postdoctoral, Massachusetts Institute of Technology

Education and Training	Ph.D., City University of New York (CUNY)
	Postdoctoral, Rockefeller University
	Postdoctoral, Massachusetts Institute of Technology

Our research has focused on elucidating the signaling mechanisms that regulate several aspects of T cell physiology including T cell development, activation and trafficking under physiologic and disease conditions. The ability of T cells to search for foreign antigens and mount an immune response is controlled by at least two important receptor systems. Engagement of the T cell receptor (TCR) by its cognate antigen triggers T cell activation and the initiation of an adoptive immune response. In order to accomplish this, T cells migrate in and out of lymphoid tissues under the direction of chemokine gradients and engagement of chemokine receptors expressed on their surface. Using gain and loss of function approaches we recently defined multi-protein complexes assembled by novel adapter proteins Sin/Efs, Chat-H and CasL/Hef1, which regulate intracellular signals in response to T cell and chemokine receptor stimulation. Sin/Efs influences signaling by sequestering cytoplasmic substrates and regulating their availability and/or activity in resting cells, while Sin is required for targeting these intermediates to the TCR for fast signal transmission during stimulation. Chat-H and CasL/Hef1 on the other hand regulate T cell migration by activating the Rap1 GTPase and integrin-mediated adhesion in response to chemokine stimulation. Localization of Chat-H to the plasma membrane, association with its binding partner CasL/Hef1, and Chat-H-mediated CasL/Hef1 phosphorylation are all required for T cell migration. We are currently using genetically engineered mice to study the signaling mechanisms which, through Chat-H and CasL/Hef1, regulate T cell migration, T cell mediated immune responses, and in vivo trafficking of T cells under normal or inflammatory conditions.

In parallel experiments we are studying the cellular and molecular mechanisms that regulate T cell tolerance and T cell-mediated autoimmunity.  T cell tolerance is exerted through two different mechanisms: a) elimination of self-reactive T cells in the thymus during selection; b) generation of regulatory T cells (Treg) which in peripheral tissues suppress the activity of self-reactive T cells that escape destruction in the thymus. Autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and diabetes arise as a result of breakdown of the mechanisms that establish tolerance to self molecules within the T cell repertoire. We recently showed that mice deficient in Sin/Efs expression develop inflammation in and autoantibodies against several tissues as they age. We are currently examining whether Sin/Efs can regulate self tolerance and how Sin/Efs deficiency may affect the production of a tolerant T cell repertoire. Our research is directed towards elucidating novel mechanisms that regulate T cell physiology. Thus, the signaling modules we identified as playing important roles in T cell activation and migration can serve as novel therapeutic targets to control the behavior of T cells in inflammation and autoimmunity.

Regelmann AG, Danzl NM, Wanjalla C, Alexandropoulos K. The hematopoietic isoform of Cas-Hef-1-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking. Immunity 2006; 25: 907-918.

Natarajan M, Stewart JE Jr., Golemis E, Pugacheva E, Alexandropoulos K, Grammer JR, Gladson CL. HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Oncogene 2006; 25: 1721-1732.

Donlin LT, Danzl N, Wanjalla C, Alexandropoulos K. Deficiency in Expression of the Signaling Protein Sin/Efs Leads to T lymphocyte Activation and Mucosal Inflammation. Mol. Cell. Biol 2005; 25: 11035-11046.

Xing L, Donlin LT, Miller RH, Alexandropoulos K. The Adapter Molecule Sin Regulates T-Cell-Receptor-Mediated Signal Transduction by Modulating Signaling Substrate Availability. Mol. Cell. Biol 2004; 24: 4581-4592.

Alexandropoulos K, Donlin LT, Xing L, Regelmann AG. Sin: Good or Bad? A T- lymphocyte perspective . Immonol. Rev 2003; 192: 181-195.

Donlin LT, Roman CA, Adlam M, Regelmann AG, Alexandropoulos K. Defective thymocyte maturation by transgenic expression of a truncated form of the adapter molecule and Fyn substrate, Sin. J. Immunol 2002; 169: 6900-6909.

Xing L, Ge C, Zeltser R, Maskevitch GR, Mayer BJ, Alexandropoulos K. c-Src signaling induced by the adapters Sin and Cas is mediated by the Rap1 GTPase. Mol. Cell. Biol 2000; 20: 7363-7377.