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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01AI035296-21
Application #
8662149
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Malhotra, Deepali; Linehan, Jonathan L; Dileepan, Thamotharampillai et al. (2016) Tolerance is established in polyclonal CD4(+) T cells by distinct mechanisms, according to self-peptide expression patterns. Nat Immunol 17:187-95
Beura, Lalit K; Hamilton, Sara E; Bi, Kevin et al. (2016) Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532:512-6
Kalekar, Lokesh A; Schmiel, Shirdi E; Nandiwada, Sarada L et al. (2016) CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nat Immunol 17:304-14
Xing, Yan; Wang, Xiaodan; Jameson, Stephen C et al. (2016) Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling. Nat Immunol 17:565-73
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:
Pritchard, Gretchen Harms; Cross, Eric W; Strobel, Marjorie et al. (2016) Spontaneous partial loss of the OT-I transgene. Nat Immunol 17:471
Grimm, Jennifer M; Schmeling, David O; Dunmire, Samantha K et al. (2016) Prospective studies of infectious mononucleosis in university students. Clin Transl Immunology 5:e94
Schmiel, Shirdi E; Yang, Jessica A; Jenkins, Marc K et al. (2016) Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination. J Immunol :
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
Manlove, Luke S; Berquam-Vrieze, Katherine E; Pauken, Kristen E et al. (2015) Adaptive Immunity to Leukemia Is Inhibited by Cross-Reactive Induced Regulatory T Cells. J Immunol 195:4028-37

Showing the most recent 10 out of 122 publications