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Research > Faculty Alphabetical > Mary Markiewicz, PhD

Assistant Professor, Pathology and Immunology
Office Suite B - 8210, BJCIH Building
Office: (314) 747-0816
Lab: (314) 362-4609
E-mail: mmarkie@pathology.wustl.edu

Research

Our research focus is determining the role of the NK cell activating receptor NKG2D and its ligands in immunity, with a particular interest on the function of this receptor-ligand system in CD8+ T cell responses.

NKG2D ligand expression in the pancreas is suggested to be a causative step in the development of autoimmune diabetes via engagement of NKG2D on CD8+ T cells. To address this issue, we generated transgenic mice with expression of an NKG2D ligand restricted to the β-islet cells of the pancreas. We found this allowed for the specific recruitment of CTL to the islets via NKG2D engagement independent of antigen recognition by the TCR. Interestingly, this resulted in the subsequent recruitment of additional lymphocytes to the islets via chemokine expression. Additionally, a mild insulitis, made up largely of lymphocytes, developed spontaneously in older transgenic mice that could be worsened by inducing pancreatic inflammation and increasing CTL numbers in the mice. These results suggest that NKG2D ligands may be involved in recruiting immune cells to the pancreas, but that other additional factors, most likely islet-specific T cells, are required to induce diabetes. Therefore, we are now turning to models in which mice develop overt diabetes to investigate the roles of NKG2D on CTL-mediated islet destruction. In addition, we are utilizing NKG2D ligand reporter mice we generated using bacterial artificial chromosome (BAC) technology to begin to characterize NKG2D ligand expression during the development of autoimmune diabetes and other diseases.

Engagement of NKG2D on NK cells or T cells by NKG2D ligands expressed on tumor cells is also proposed to be important in the control of tumor growth by the immune system. Consistent with this, transgenic mice we generated with ubiquitous expression of an NKG2D ligand have decreased NKG2D expression and increased spontaneous lymphoma development. We are now using these mice to gain insight into the role of NKG2D in tumor immunosurveillance.


Selected Publications:

Cheney, EE, Wise, EL, Bui, JD, Schreiber, RD, Carayannopoulos, LN, Spitzer, D, Zafirova, B, Polic, B, Shaw AS, and Markiewicz, MA. A dual function of NKG2D ligands in NK-cell activation. Eur J Immunol 2012; 42:2452.

Markiewicz, MA, Wise, EL, Buchwald, ZS, Pinto, AK, Zafirova, B, Polic, B, Shaw, AS. Antigen-independent recruitment of CTL to pancreatic islets expressing an NKG2D ligand. Immunity 2012; 36:132.

Markiewicz MA, Wise EL, Buchwald ZS, Cheney EE, Hansen TH, Suri A, Cemerski S, Allen PM, Shaw AS. IL-12 Enhances CTL Synapse Formation and Induces Self-reactivity. J Immunol 2009; 182:1351.

Cemerski S, Das J, Giurisato E, Markiewicz MA, Allen PM, Chakraborty, AK, Shaw AS. The balance between T cell receptor signaling and degradation at the center of the immunological synapse is determined by antigen quality. Immunity 2008; 29:414.

Cermerski, S, Das J, Locasale J, Arnold P, Giurisato E, Markiewicz MA, Fremont D, Allen PM, Chakrabory AK, Shaw AS. The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse. Immunity 2007; 26:345

Markiewicz MA, Carayannopoulos LN, Naidenko OV, Matsui K, Burack WR, Wise EL, Fremont DH, Allen PM, Yokoyama WM, Colonna M, Shaw AS. Costimulation through NKG2D enhances murine CD8+ CTL function: similarities and differences between NKG2D and CD28 costimulation. J Immunol 2005;175:2825

Lee KH, Dinner AR, Tu C, Campi G, Raychaudhuri S, Varma R, Sims TN, Burack WR, Wy H, Wang J, Kanagawa O, Markiewicz M, Allen PM, Dustin ML, Chakraborty AK, Shaw AS. The immunological synapse balances T cell receptor signaling and degradation. Science 2003;302:1218

Markiewicz MA, Brown I, Gajewski TF. Death of peripheral CD8+ T cells in the absence of MHC class I is Fas-dependent and not blocked by Bcl-XL. Eur J Immunol 2003;10:2917

Markiewicz MA, Girao C, Opferman JT, Sun J, Hu Q, Agulnik AA, Bishop CE, Thompson CB, Ashton-Rickardt PG. Long-term T cell memory requires the surface expression of self-peptide/major histocompatibility complex molecules. Proc Natl Acad Sci USA 1998;95:3065