Tissue Immune Regulation
Autoimmunity is an inflammatory condition caused by immune cells attacking harmless (self-) antigens in host tissues, which they are supposed to protect. Conversely, cancer is a disease in which altered self-cells are not cleared from the tissue and are thus allowed to multiply. We hypothesize that autoimmunity is a result of exaggerated immunity while cancer results from exaggerated regulatory/suppressive responses. Thus both diseases might result from an inappropriate balance between inflammation and regulation in the target tissue. However, further basic research is required to fully understand immune-regulatory processes in the target tissues.
Our research aims to elucidate the mechanisms that control the balance of immune activation versus tolerance, which ultimately determines the outcome and severity of disease. Understanding these mechanisms will help to develop novel therapeutic strategies.
In our studies we focus on immune-regulatory processes of a major epithelial body surface, the skin.
Our main research questions are:
1. The role of Foxp3+ regulatory T cells (Treg) in inflammation, their generation and recruitment to the target tissue.
2. Immune cell stability and memory formation of T cells with an emphasis on epigenetic processes and their regulation by the milieu (such as co-stimulatory and co-inhibitory molecules and cytokines).
In our projects we study cellular processes of T cell differentiation, focusing on the fate decision between IFN-γ producing T helper 1 cells and Foxp3+ Treg cells. For these studies we use innovative mouse models, which allow us to follow and manipulate T cell responses to neo-antigens (e.g. altered self) in vivo. We combine the use of these transgenic and knock-out mice with the application of biologics, antibodies and small molecule drugs to manipulate immune cells in vivo.
In all of our approaches we focus not only on the phenotypes of selected immune cell subtypes but also on the crosstalk between the target tissue immune cells, particularly the interaction between tissue cells, T cells and tissue-derived antigen-presenting cells (APCs).
Rosenblum MD*, Gratz IK*, Paw JS, Lee K, Marshak-Rothstein A, Abbas AK. Response to self antigen imprints regulatory memory in tissues. Nature. 2011
Gruber C, Gratz IK, Murauer EM, Mayr E, Koller U, Bruckner-Tuderman L, Meneguzzi G, Hintner H, Bauer JW Spliceosome-mediated RNA trans-splicing facilitates targeted delivery of suicide genes to cancer cells. Mol Cancer Ther. 2011 Feb
Ettinger M, Peckl-Schmid D, Gruber C, Laimer M, Thalhamer J, Hintner H, Gratz IK* and Bauer JW* Transcutaneous gene gun delivery of NC16A induces BPAG2-specific tolerance. J Invest Dermatol. 2012
Gratz IK, Truong HA, Yang SH, Maurano MM, Lee K, Abbas AK, Rosenblum MD. Cutting Edge: memory regulatory t cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J Immunol. 2013
Gratz IK, Rosenblum MD, Maurano MM, Paw JS, Truong HA, Marshak-Rothstein A, Abbas AK. Cutting Edge: Self-Antigen Controls the Balance between Effector and Regulatory T Cells in Peripheral Tissues. J Immunol. 2014
Scharschmidt TC, Vasquez KS, Truong HA, Gearty SV, Pauli ML, Nosbaum A, Gratz IK, Otto M, Moon JJ, Liese J, Abbas AK, Fischbach MA, Rosenblum MD. A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes. Immunity. 2015
Iris Gratz, PhD
Department of Biosciences
University of Salzburg
Regulation of T cell responses by the local milieu (cytokines, TLRs, damage, etc.) in Cancer and Autoimmunity. Depending on the activation status of antigen-presenting cells (APC) APC-derived cytokines can either promote regulatory T cells or effector T cells (such as Th1 and Th17). Thus, activation of APC to induce Th17, Th1 and Treg polarization can either favor or counter autoimmunity, respectively. Correspondingly, the balance between effector versus regulatory T cell activation can determine the magnitude of anti-tumor responses.