This core will make important resources available to all Projects of this PPG. The nanowell technology represents a powerful tool to study the functional consequences of interactions between T cells and APC. The technology will enable in-depth investigation of the impact of different types of APCs on the functional programs of self-reactive T cells, which is of central importance to this PPG. A novel feature of this technology is that the functional consequences on both T cells and APC can be studied for interacting cell pairs, offering insights into the complex communication that programs self-reactive T cells with autoaggressive behavior. This core will enable integration of datasets from clinical specimens and experimental mouse models (Aim 1). It provides an important link between Projects 1 and 2, which both study myelin-specific T cells from patients with MS. The technology enables robotic isolation of cells of interest, such as myelin-specific T cells that produce combinations of pro-inflammatory cytokines (e.g. IL-17 + GM-CSF), for analysis of single-cell gene expression or clonal expansion. Furthermore, the technology will be made available for analysis of murine T cells, APCs and stromal cells (Projects 3 and 4). The core will also make recombinant proteins available to all Projects of this PPG, including experiments in the nanowell system (Aim 2), This core has provided such reagents to all Projects in the previous funding period and will continue to provide them for several efforts: 1. Studies by Dustin and Wucherpfennig have examined immunological synapse formation by human self-reactive T cells using the planar lipid bilayer system developed by the Dustin lab. Recent collaborative studies by the Love and Wucherpfennig labs have applied this approach to the nanowell system, enabling synapse structure to be related tp T cell function. These experiments require sets of human and murine recombinant proteins, including peptide-MHC complexes, ICAM-1 and CD80 (Projects 1 and 2). 2. Collaborative studies by the Kuchroo and Wucherpfennig labs have shown that tetramers of the MOG extracellular domain can be used to label MOG-specific B cells, and this reagent will be used in Project 3. 3. The turley, Kuchroo and Wucherpfennig labs have utilized Ig fusion proteins of podoplanin and CLEC-2 to study the function of these molecules in T cell - APC communication, which will be provided to Projects 3 and 4. This core will thus enable in-depth investigation of T cell - APC interactions in both humans and animal models to advance our understanding ofthe pathogenesis of MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI045757-15
Application #
8583040
Study Section
Special Emphasis Panel (ZAI1-MM-I (M1))
Project Start
2013-09-01
Project End
2018-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
15
Fiscal Year
2013
Total Cost
$217,400
Indirect Cost
$51,872
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Urso, Katia; Alvarez, David; Cremasco, Viviana et al. (2016) IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease. JCI Insight 1:
Adams, Jarrett J; Narayanan, Samanthi; Birnbaum, Michael E et al. (2016) Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity. Nat Immunol 17:87-94
Longbrake, Erin E; Hafler, David A (2016) Linking Genotype to Clinical Phenotype in Multiple Sclerosis: In Search of the Holy Grail. JAMA Neurol 73:777-8
Singer, Meromit; Wang, Chao; Cong, Le et al. (2016) A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells. Cell 166:1500-1511.e9
Fernandez-Carbonell, Cristina; Vargas-Lowy, David; Musallam, Alexander et al. (2016) Clinical and MRI phenotype of children with MOG antibodies. Mult Scler 22:174-84
Cao, Yonghao; Nylander, Alyssa; Ramanan, Sriram et al. (2016) CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. Neurology 86:1553-6
Axisa, Pierre-Paul; Hafler, David A (2016) Multiple sclerosis: genetics, biomarkers, treatments. Curr Opin Neurol 29:345-53
Lowther, Daniel E; Goods, Brittany A; Lucca, Liliana E et al. (2016) PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 1:
Chastre, Anne; Hafler, David A; O'Connor, Kevin C (2016) Evaluation of KIR4.1 as an Immune Target in Multiple Sclerosis. N Engl J Med 374:1495-6
Astarita, Jillian L; Cremasco, Viviana; Fu, Jianxin et al. (2015) The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nat Immunol 16:75-84

Showing the most recent 10 out of 117 publications