Investigator Spotlight: Helena Reijonen, Ph.D.

Identification of T cell characteristics associated with type 1 diabetes and its triggering in humans is very challenging. For the most part, T cell studies in human subjects can be done using peripheral blood samples. Not only is the frequency of autoreactive T cells in the circulation low, but it is unclear how well the peripheral blood represents the diversity of T cell repertoire relevant to the disease pathogenesis. nPOD network has provided an outstanding opportunity to access precious samples from the pancreas and pancreatic lymph nodes of T1D patients and individuals with underlying islet autoimmunity. This unique opportunity facilitates the studies of T cells that are present in the inflammatory lesion, and also contributes to understanding distinct stages of the ongoing autoimmunity.

We and others have shown that islet autoantigen specific T cells can be found in both T1D patients and healthy individuals.  However, these T cells with the same antigen specificity are expected to differ in their phenotypic characteristics such as memory status, homing and cytokine profiles. Also, some immunodominant epitopes from diabetes associated autoantigens (GAD65, proinsulin/insulin, Zn-T8) can bind and be presented by both risk and protection associated MHC class II molecules. We have generated MHC class II tetramers that allow identification of T cell populations reacting against specific islet autoantigens and are restricted by either  susceptibility or protective HLA variants.  Another advantage of our tetramer-based technology is the ability to determine the functional phenotype of autoantigen specific T cells, for example memory, avidity/affinity, cytokine profiles, homing properties and clonotypic diversity. 

Our hypothesis is that T cell responses to the same autoantigen can be either protective or pathogenic depending on the nature of the response. We hypothesize that in healthy individuals T cells with immunoregulatory or anti-inflammatory phenotype are preferentially activated early in the primary autoimmune process when quantity of antigen is limiting which keeps the expansion of the diabetogenic T cells under control.  We aim to identify and compare the autoreactive T lymphocytes and their biological features in the local lymph nodes, spleen and blood from nPOD organ donors with different stages of islet autoimmunity.  We will also study the role of bone marrow derived T lymphocytes in the disease process from samples that have recently become available to nPOD investigators. There is growing interest in the role of bone marrow derived T cells in autoimmunity and long-term memory but this area has not been previously studied in human T1D due to unavailability of tissue samples.  The role of bone marrow derived T cells is intriguing in staging the disease process but also in long-term T1D patients who have been shown to have persistent a T cell memory cell population capable of being activated decades after the disease onset.

nPOD samples from T1D patients with a different duration of the disease, autoantibody positive individuals and healthy controls with known genetic background offer a unique opportunity to study pathology of type 1 diabetes at different stages of the disease.  Collaboration with other nPOD investigators allows this project to generate new knowledge on the key features and the population dynamics of T cells directly associated with islet autoimmunity, functional disease mechanisms and beta-cell biology in human diabetes. This is a goal that formerly was possible to reach only by using experimental animal models.