Only T cells with the capacity to bind to self-peptide MHC complexes (self-reactivity) are included in the repertoire because of positive selection. And yet, self-reactivity is also the perilous feature of T cells that cause autoimmune disease. The distinction between useful and dangerous T cells is a matter of degree, with T cells that have a low affinity for self-MHC being useful, and those that have high affinity for self-MHC being dangerous. Yet to date, it has not been possible to study or measure the self-reactivity of diverse polyclonal populations of T cells. We propose to use a novel Nur77GFP BAC transgenic reporter mouse, in combination with tetramer enrichment and various gene deficiency models to quantitative self-reactivity in polyclonal T cells from normal and autoimmune disease prone animals. The three specific aims are: 1) to enumerate and study the T cells that are normally clonally deleted, 2) to define the contribution of CD28, medullary epithelial cells, and dendritic cells to negative selection in the thymus, and 3) to identify and characterize the self-reactive T cells that are present in diabetes-prone mice.
Autoimmune disease is major human health problem whose origins are not well understood, and for which new treatments are strongly needed. This project is relevant because it attempts to identify and study the pool of T lymphocytes that autoimmune disease causing T cells arise from.
|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-ÎºB 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