Lymphocyte dynamics in lymph nodes are governed by environmental GO signals and STOP signals that interact with intrinsic polarity networks in the cell. Chemokine receptors are a major class of G-protein coupled receptors and CCR7 is the most important member of this class of receptors for delivering GO signals to naive effector T cells (Teff) in secondary lymphoid tissues. Each antigen receptor can interact with a spectrum of MHC-peptide complex ligands that vary in potency and can be presented over a wide range of concentrations on varying numbers of dendritic cells to deliver STOP signals. Signaling to polarity networks is mediated in part by protein kinase C- 8 (PKC-8), which induces symmetry breaking and conversion of stable synapses to mobile kinapses. While Teff cells activate PKC-8 in response to antigen, regulatory T cells (Treg) inactivate PKC-8 in response to antigen, suggesting distinct control of polarity by TCR signals. Our hypothesis is that particular configuration of GO and STOP and Treg PKC-8 signals lead to failure of peripheral tolerance to low potency ligands that can become autoantigens in the context of tissue injury or inflammatory stimuli. First, we will determine the effect of eliminating GO signals on Teff responses to a spectrum of ligands for a well-studied T cell receptor system. Second, we will examine the structural aspects of T cell responses to high and low potency ligands and quantify the impact of antigen presenting dendritic cell frequency on tolerance induction. Third, we will investigate the role of PKC-8 in control of Treg interactions with DC and Teff in vivo and in vitro. The results of these studies will fill major gaps in our understanding of how Teff and Treg interactions are regulated in lymph nodes and at effector sites, which is key maintaining peripheral tolerance and preventing autoimmunity.

Public Health Relevance

Vaccination strategies depend upon a physical embrace between antigen specific T lymphocytes and antigen presenting dendritic cells. We hypothesize that the stability of this embrace will depend upon the quality of antigen that defines a stop signal for the migrating T cell, signals in the environment that provide a competing go signal to the lymphocyte and polarity networks controlled by kinases. We propose experiments to determine the roles of chemokines, dendritic cell frequency and regulatory T cell protein kinase C-8 in tolerance induction.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG1-IMM-F (02))
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Lapham, Cheryl K
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New York University
Schools of Medicine
New York
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Coles, Jonathan A; Stewart-Hutchinson, Phillip J; Myburgh, Elmarie et al. (2017) The mouse cortical meninges are the site of immune responses to many different pathogens, and are accessible to intravital imaging. Methods 127:53-61
Jang, Jung-Eun; Hajdu, Cristina H; Liot, Caroline et al. (2017) Crosstalk between Regulatory T Cells and Tumor-Associated Dendritic Cells Negates Anti-tumor Immunity in Pancreatic Cancer. Cell Rep 20:558-571
Shaw, Tovah N; Stewart-Hutchinson, Phillip J; Strangward, Patrick et al. (2015) Perivascular Arrest of CD8+ T Cells Is a Signature of Experimental Cerebral Malaria. PLoS Pathog 11:e1005210
Mayya, Viveka; Neiswanger, Willie; Medina, Ricardo et al. (2015) Integrative analysis of T cell motility from multi-channel microscopy data using TIAM. J Immunol Methods 416:84-93
Kuan, Emma L; Ivanov, Stoyan; Bridenbaugh, Eric A et al. (2015) Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells. J Immunol 194:5200-10
Choudhuri, Kaushik; LlodrĂ¡, Jaime; Roth, Eric W et al. (2014) Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 507:118-23
Dustin, Michael L (2014) The immunological synapse. Cancer Immunol Res 2:1023-33
Williams, Cassandra R; Dustin, Michael L; Sauer, John-Demian (2013) Inflammasome-mediated inhibition of Listeria monocytogenes-stimulated immunity is independent of myelomonocytic function. PLoS One 8:e83191
Waite, Janelle C; Vardhana, Santosh; Shaw, Patrick J et al. (2013) Interference with Ca(2+) release activated Ca(2+) (CRAC) channel function delays T-cell arrest in vivo. Eur J Immunol 43:3343-54
Ruocco, Maria Grazia; Pilones, Karsten A; Kawashima, Noriko et al. (2012) Suppressing T cell motility induced by anti-CTLA-4 monotherapy improves antitumor effects. J Clin Invest 122:3718-30

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