Marrero, Idania , Ph.D.
Characterization of TCR repertoires of memory CD4 T cells --- avidity, competition and diversity of specificity in the autoimmune context of NOD mice
General Research Subject: Type 1 Diabetes
Focus: Immunology, Transplantation
Type of Grant: Junior Faculty
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Diabetes Type: Type 1 diabetes
After contact with a particular antigen, memory T cells can divide very fast and increase their potential to induce damage. Others have shown that memory cells can play an important role in Type 1 Diabetes (T1D). However, different aspects of the repertoire of memory CD4 T cells have yet to be explored. We will use a powerful technology capable of identifying thousands of different T cell receptors, which, in combination with single cell analysis and functional markers, will allow us to study memory CD4 T cells. Our overall study includes: defining the identity and specificities of memory CD4 T cells that emerge during progression toward diabetes in NOD mice to study the natural memory CD4 T cell repertoire; characterizing the memory cell populations that migrate to the islet graft where they can be reactivated to destroy the graft as new islet antigens are expressed upon islet transplantation. We will study how to protect the islet grafts from recurrent autoimmunity. Also, we will study the functional role of memory T cell clones that have the capacity to respond against different antigens, which means that they show polyspecificity in their recognition of antigen. These cells can be the winner in the competition for antigen in the pancreas and then can represent a very dangerous population for T1D patients. I expect to identify the most relevant T cell clones inside the pool of memory CD4+ T cells and their biological functions in the NOD model of T1D.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My project covers the study of immunology in diabetes and islet transplantation. My work will be focused on identify aggressive immune cells called memory CD4 T cells. These memory T cells are important in that they actively destroy islet cells and can be reactivated following islet transplantation. We expect to discover and characterize T cell clones within the pool of memory CD4 T cells that are relevant to T1D. There is significant hope that this project can be directed towards therapeutic strategies to inhibit, neutralize or destroy aggressive memory T cells that are involved in recurrent autoimmunity after islet transplantation.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project will study immune cells in Type 1 Diabetes (T1D). The cells in the pancreas that make insulin, islet cells, are destroyed by aggressive T lymphocytes. The aggressive T cells that live for a long time and are called memory cells can be reactivated to destroy new islets after islet transplantation. We will use a powerful technology capable of identifying thousands of different receptors on the surface of memory T cells, which, in combination with single cell analysis and functional markers, will allow us to define the identity of the natural memory cell repertoire that emerge during progression toward diabetes and determine which members of the memory cell populations are responsible for islet graft destruction. We will be able to identify dangerous cell populations for T1D patients and foresee new therapeutic treatments to protect the islet grafts from damage.
I will use the NOD mouse which develops T1D spontaneously and shares many characteristics with the human disease to investigate the identity, emergence and relevance of T cell clones inside the pool of memory T cells and their biological functions in the NOD model of T1D.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have been involved in diabetes research throughout my postdoctoral career. Research in Type 1 Diabetes has been particularly important to me because I have the opportunity to apply the knowledge that I have gained regarding the basic immunological pathways to clinical medicine. It is my hope that knowledge gained in the study proposed will have a direct impact on the treatment and/or prevention of T1D and, more specifically, recurrent autoimmunity after islet transplantation. Specifically, we hope to gain new knowledge that will indicate how to suppress the memory CD4 T cells that usually destroy beta cells in the pancreas and cause recurrent autoimmunity in islet grafts. This award will allow me to continue my career in diabetes research and explore new pathways involved in islet destruction that might be exploited to provide new therapeutic strategies and hope for successful treatments.
In what direction do you see the future of diabetes research going?
The future of diabetes research will be dependent on our capacity to translate the discovery of basic research to clinical practice. It is critical that we share our knowledge and promote strong collaborations in the scientific community. From our point of view, it will be important to combine molecular approaches, and sophisticated technology with the more basic approach of understanding the identity of the effectors cells that are involved in T1D.
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