Theses
Date of Award
2025
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Biological Sciences
First Advisor
Teresa DiLorenzo
Second Advisor
Kristina Ames
Abstract
The immune system is the body’s defense mechanism against infections. The lymphoid lineage of the immune system responds to infections using B and T cells. CD8 T cells, also known as cytotoxic T cells, are cells of the immune system that originate from the hematopoietic stem cells of the bone marrow. The role of CD8 T cells is to kill virally infected cells. However, in some cases, CD8 T cells attack normal cells in the body, causing autoimmune diseases like type 1 diabetes (T1D). In T1D, CD8 T cells attack and kill beta cells in the islets of the pancreas, resulting in the body's inability to produce insulin, which is needed for the breakdown of glucose to produce energy. However, before CD8 T cells can bind to an infected or healthy cell, peptides of that cell need to be presented by cell-surface glycoproteins known as class I major histocompatibility complex (MHC) molecules. In humans, MHC molecules are known as Human Leukocyte Antigens (HLA).
Previous studies have been conducted in mice to study two human class I MHC molecules associated with T1D, HLA-A2 and HLA-B39. Using transgenic mouse models that expressed either HLA-A2 or HLA-B39 in the absence of the mouse class I MHC, it was found that each human MHC alone was sufficient to mediate T1D, but only in approximately 50% of the mice. To more closely mimic humans, who express multiple class I MHC molecules, we introduced both HLA-A2 and HLA-B39 in the same mouse model. We found that the mice are T1D-susceptible, making this a new human-relevant spontaneous model for T1D. The influence of the expression of both HLA-A2 and HLA-B39 class I MHC molecules in T1D development was tested by developing NOD mice that express both HLA-A2 and HLA-B39 by intercrossing the two single-transgenic strains. We assessed T1D development in the new mouse strain by conducting an incidence study. Although still ongoing, this study suggests that mice expressing both HLA-A2 and HLA-B39 in the absence of the mouse class I MHC show a higher T1D susceptibility than the single-transgenic strains. As a next step, we will identify the peptides recognized by the islet-infiltrating CD8 T cells in the double-transgenic model.
Moreover, to study the role of CD8 T cells and class I MHC in infectious diseases, we used the Syrian hamster as our model system. The Syrian hamster has been used to study a number of viruses and other pathogens due to the similarities in disease symptoms, pathogenesis, and immune response they share with humans. Surprisingly though, there are no known hamster MHC’s that we can use to study infectious diseases. However, our lab has identified two candidate hamster class I MHC genes (K and D) that we are characterizing to fill this knowledge gap. We have determined the credibility of the hamster class I MHC K candidate and verified that it is a class I MHC molecule. As a next step, the K molecules will be purified and the peptides that they present will be characterized.
The identification of peptides recognized by CD8 T cells in our humanized T1D mouse model expressing both HLA-A2 and HLA-B39 could lead to new diagnostic or therapeutic strategies in humans. The discovery of the class I MHC molecules in hamsters will facilitate advanced T cell studies related to pathogenesis and the development of improved vaccines for infectious diseases. Overall, our work contributes to our understanding of the dual role of CD8 T cells of the immune system in T1D and infectious diseases.
Recommended Citation
Brew, Isabella, "Class I MHC in Infectious Diseases and Autoimmunity" (2025). CUNY Academic Works.
https://academicworks.cuny.edu/le_etds/42
