Mary A. Markiewicz, Ph.D.
Microbiology, Molecular Genetics & Immunology
Ph.D., University of Chicago, Chicago, IL, USA, 2001
Postdoctoral Fellow, Washington University School of Medicine, St. Louis, MO, USA
Publications: Click here
My lab's research focus is to determine the role of the NK cell activating receptor NKG2D and its ligands in various types of immunity, with a particular interest on the function of this receptor-ligand system in CD8+ T cell responses. Our two current projects involve understanding the role of NKG2D signaling in autoimmune diabetes and tumor immunity.
NKG2D and autoimmune diabetes
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 are required to induce diabetes. Therefore, we have now turned to models in which mice develop overt diabetes to investigate the roles of NKG2D in immune-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.
NKG2D and tumor immunity
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, which have decreased NKG2D expression, have increased spontaneous lymphoma development. We are now using these mice to gain insight into the mechanism by which NKG2D-NKG2D ligand interaction functions in tumor immunosurveillance.
Raju S, Kretzmer LZ, Koues OI, Payton JE, Oltz EM, Cashen A, Polic B, Schreiber RD, Shaw AS, Markiewicz MA. NKG2D-NKG2D Ligand Interaction Inhibits the Outgrowth of Naturally Arising Low-Grade B Cell Lymphoma In Vivo. J Immunol. 2016 Jun 1;196(11):4805-13. doi: 10.4049/jimmunol.1501982. Epub 2016 May 2.
Chung JJ, Markiewicz MA, Polić B, Shaw AS. Role of NKG2D in obesity-induced adipose tissue inflammation and insulin resistance. PLoS One. 2014 Oct 15;9(10):e110108. doi: 10.1371/journal.pone.0110108. eCollection 2014. PMID: 25333972
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 MA, 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