In previous work under this grant, we discovered that inflammatory cytokines provide a 'third signal'that determines whether antigen recognition by naive CDS T cells leads to tolerance or full activation and memory, with IL-12 and Type I IFN being the critical cytokines. More recent work has shown that early autocrine production of IFN? can signal for some limited differentiation of naive CD8 T cells so that they develop weak effector functions but do not survive long term. We have also obtained evidence showing that the potential for inhibitory receptors (PD-1) to tolerize CD8 T cells by 'exhaustion'differs depending on whether the cells initially responded in the presence of IL-12 or Type I IFN. Based on these findings, we now plan to study the roles of self-antigen-specific CD8 T cells in the development of Type I autoimmune diabetes in the non-obese diabetic (NOD) mouse model. We will examine the hypothesis that short-lived, weak effector CDS T cells that differentiate in response to IFN? play a critical role in initiating diabetes by making Ag available to activate CD4 T-helper cells. We will also examine the hypothesis that, upon activation, CD4 T-helper cells will stimulate dendritic cells to produce IL-12 and/or Type I IFN to support development of a strong, long-lived effector CD8 response that causes disease and the hypothesis that effector CD8 T cells may differ in their diabetogenic potential due to differing levels of PD-1 expression depending on which signal 3 cytokine drives their differentiation. In addition, preliminary evidence suggests that CD8 T cells of NOD mice may, in comparison to other strains, have a decreased dependence on a third signal from IL-12 or Type I IFN to undergo differentiation leading to strong effector functions. The possibility that this may contribute to the loss of tolerance to self-antigen in NOD mice will be studied. We anticipate that our planned studies will lead to a better understanding of the mechanisms by which CDS T cell tolerance to self-antigen is lost to result in the development of Type I autoimmune diabetes;information that will likely have application to development of immunotherapies for prevention and therapy of autoimmunity.
This project examines mechanisms of tolerance induction versus activation of self-antigen-specific CDS T cells in autoimmune disease. Innovative technologies developed by this Program will be used to explore novel concepts regarding the roles of CDS T cells in diabetes, and the findings will contribute to development of better approaches for preventing or treating autoimmune diseases.
|Spanier, Justin A; Sahli, Nathanael L; Wilson, Joseph C et al. (2017) Increased Effector Memory Insulin-Specific CD4+ T Cells Correlate With Insulin Autoantibodies in Patients With Recent-Onset Type 1 Diabetes. Diabetes 66:3051-3060|
|Kalekar, Lokesh A; Mueller, Daniel L (2017) Relationship between CD4 Regulatory T Cells and Anergy In Vivo. J Immunol 198:2527-2533|
|Breed, Elise R; Lee, S Thera; Hogquist, Kristin A (2017) Directing T cell fate: How thymic antigen presenting cells coordinate thymocyte selection. Semin Cell Dev Biol :|
|Burrack, Adam L; Martinov, Tijana; Fife, Brian T (2017) T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes. Front Endocrinol (Lausanne) 8:343|
|Ruscher, Roland; Kummer, Rebecca L; Lee, You Jeong et al. (2017) CD8?? intraepithelial lymphocytes arise from two main thymic precursors. Nat Immunol 18:771-779|
|Schmiel, Shirdi E; Yang, Jessica A; Jenkins, Marc K et al. (2017) Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination. J Immunol 198:623-628|
|Spanier, Justin A; Frederick, Daniel R; Taylor, Justin J et al. (2016) Efficient generation of monoclonal antibodies against peptide in the context of MHCII using magnetic enrichment. Nat Commun 7:11804|
|Martinov, Tijana; Spanier, Justin A; Pauken, Kristen E et al. (2016) PD-1 pathway-mediated regulation of islet-specific CD4(+) T cell subsets in autoimmune diabetes. Immunoendocrinology (Houst) 3:|
|Tubo, Noah J; Fife, Brian T; Pagan, Antonio J et al. (2016) Most microbe-specific naïve CD4? T cells produce memory cells during infection. Science 351:511-4|
|Pritchard, Gretchen Harms; Cross, Eric W; Strobel, Marjorie et al. (2016) Spontaneous partial loss of the OT-I transgene. Nat Immunol 17:471|
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