Mary Markiewicz

Research

Overview

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

Type 1 diabetes is an autoimmune disease in which the β cells in pancreatic islets are destroyed. The current standard of care for this disease, insulin replacement, is cumbersome and the life expectancy of type 1 diabetes patients is still reduced compared with healthy individuals. The main drivers of type 1 diabetes are islet-specific T cells. These cells must escape a myriad of tolerance mechanisms that control their activation in healthy individuals. Understanding these mechanisms is critical to developing better strategies to inhibit the disease. One pathway implicated in this process is signaling through the Natural Killer Group 2 member D (NKG2D) immune receptor. However, the importance of NKG2D to diabetes is unclear owing to conflicting results in studies with the non-obese diabetic (NOD) mouse model. Our published data demonstrate that these inconsistent findings are likely due to differential effects of NKG2D on diabetes in different anatomical sites. Therefore, we have developed novel experimental approaches are required to determine the role NKG2D plays in various organs during diabetes development. Our data using these models demonstrate that increasing NKG2D signaling within the pancreas protects against diabetes, whereas eliminating NKG2D signaling in the pancreas enhances diabetes. Further, we show that the NKG2D-mediated protection is associated with an increase in CD8+ central memory T cells in vivo, which correlates with NKG2D-mediated generation of CD8+ central memory cells (Tcm) in vitro, and that CD8+ Tcm protect against NOD diabetes in vivo. Therefore, we are currently testing the hypothesis that NKG2D signaling on CD8+ T cells protects against diabetes by enhancing the generation of a protective CD8+ Tcm population.

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. However, NK cells and T cells also express NKG2D ligands themselves; the role for this expression in immune responses has not been determined. We are currently investigating how this NKG2D ligand expression on NK cells and T cells affects to the ability of these cells to kill tumor cells.

• Seng, Amara, Krausz, Kelsey., L, Pei, Dong, Koestler, Devin., C, Fischer, Ryan., T, Yankee, Thomas., M, Markiewicz, Mary., A. 2020. Co-expression of FOXP3 and a Helios isoform enhances the effectiveness of human engineered regulatory T cells. Blood Advances
• Trembath, Andrew., P, Sharma, Neekun, Gerling, Ivan., C, Mathews, Clayton., E, Markiewicz, Mary., A. 2020. NKG2D signaling within the pancreatic islets reduces NOD diabetes by enhancing central memory CD8+ T cell generation . Diabetes
• Trembath, A., P, Sharma, N, Raju, S, Polić, B, Markiewicz, M., A. 2017. A Protective Role for NKG2D-H60a Interaction via Homotypic T Cell Contact in Nonobese Diabetic Autoimmune Diabetes Pathogenesis.. ImmunoHorizons, 1 (9), 198-212
• Sharma, N, Trinidad, C., V, Trembath, A., P, Markiewicz, M., A. 2017. NKG2D Signaling between Human NK Cells Enhances TACE-Mediated TNF-α Release.. Journal of immunology (Baltimore, Md. : 1950), 199 (8), 2865-2872
• Raju, S, Kretzmer, L., Z, Koues, O., I, Payton, J., E, Oltz, E., M, Cashen, A, Polic, B, Schreiber, R., D, Shaw, A., S, Markiewicz, M., A. 2016. NKG2D-NKG2D Ligand Interaction Inhibits the Outgrowth of Naturally Arising Low-Grade B Cell Lymphoma In Vivo.. Journal of immunology (Baltimore, Md. : 1950), 196 (11), 4805-13