This PPG was initiated in 1998 in response to a RFA for """"""""Human Immunology Centers of Excellence"""""""" and has a well-defined, central focus on the mechanisms of antigen presentation and T cell recognition in human autoimmune diseases, in particular multiple sclerosis (MS) and type 1 diabetes (T1D). Antigen presentation is an integral component of every autoimmune disease process and thus represents an important scientific and clinical problem. The six investigators who come together in this PPG have highly complementary areas of expertise and have formed a cohesive, multidisciplinary program under the guidance of the Program Director. During the present funding period this group has been highly productive, documented by numerous joint publications that have had a significant impact on the field. The overarching hypothesis is that the development and progression of autoimmune diseases are controlled by specialized populations of antigen presenting cells that serve distinct roles in tolerance induction versus propagation of autoimmunity. There are four major themes that connect the individual projects of this PPG. A previously unrecognized population of lymph node stromal cells with functional similarities to thymic medullary epithelial cells induces peripheral tolerance by expression of a wide variety of peripheral tissue antigens, and the biology of this cell population and potential therapeutic applications will be investigated (Projects 1 &2). The role of self-reactive B cells as efficient antigen presenting cells for T cells with the same specificity will be examined in a new mouse model that resembles a severe subtype of MS. New technologies, including a nanowell technique for functional definition of B cell populations at a single cell level and fluorescent self-antigen tetramers, will be used to define the functional properties of self-reactive B cells in patients with MS and T1D (Projects 3 &4). Particular emphasis will be placed on definition of the antigen presentation mechanisms responsible for T cell differentiation into regulatory and effector T cell subsets (Projects 1-3) and on characterization of the unique recognition and signaling properties of self-reactive T cells isolated from patients with MS and T1D (Projects 1 &4). During the past two funding cycles, the program has already had an impact on the development of therapeutics, and the areas of investigation for the next funding period offer a significant number of new opportunities. PROJECT 1: Antigen Presentation to Self-reactive T cells in Human Autoimmune Diseases (PL: Kai W. Wucherpfennig, MD, PhD) DESCRIPTION (provided by applicant): The goal of the project is to define the antigen presentation and T cell recognition mechanisms responsible for the activation of myelin-specific CD4 T cells in MS. During this funding period, the Project Leader's (PL) lab determined the crystal structure of the first human autoimmune TCR and identified an unusual TCR binding topology. Biochemical studies demonstrated a low affinity interaction of this TCR with its self-peptide/MHC complex, consistent with the suboptimal binding mode observed in the structure. Such a suboptimal binding mode may facilitate escape from tolerance induction in the thymus and periphery because the relevant antigen presenting cells express limiting quantities of self-antigen. Transgenic mice that express this TCR and the human MHC restriction element nevertheless develop spontaneous autoimmunity at a high incidence, indicating that these T cells have recognition/signaling mechanisms that at least partially compensate for the altered TCR interaction with self-peptide/MHC. Imaging studies demonstrated substantial differences in the organization of immunological synapses formed by two different myelin-specific human T cell clones compared to two anti-viral T cell clones. During the next funding period, we will determine how the altered TCR recognition properties affect the formation of immunological synapses and resulting signaling events.
In Aim 1, we will define the mechanisms of immunological synapse formation by examining the kinetics of synapse formation, the recruitment of key signaling molecules, the duration of signaling as well as the mechanisms that terminate signaling by TCR internalization. Our hypothesis is that the suboptimal TCR binding properties delay TCR transport to the synapse center where TCR is internalized, thus extending the duration of the initially weaker activation signal.
In Aim 2, we will examine how these changes quantitatively modify the contribution of particular signaling pathways in self-reactive versus anti-viral T cells, with the goal of identifying signaling molecules that are critical for the activation of self-reactive T cells but dispensable for anti-viral T cells.
In Aim 3, we will examine whether tolerance can nevertheless be induced for such T cells by targeted delivery of the self-peptide via an antibody-peptide fusion protein to lymph node stromal cells specialized in peripheral tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
3P01AI045757-10S1
Application #
7897291
Study Section
Special Emphasis Panel (ZAI1-SR-I (S2))
Program Officer
Esch, Thomas R
Project Start
2009-08-13
Project End
2010-08-12
Budget Start
2009-08-13
Budget End
2010-08-12
Support Year
10
Fiscal Year
2009
Total Cost
$64,414
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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Ponath, Gerald; Lincoln, Matthew R; Levine-Ritterman, Maya et al. (2018) Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. Nat Commun 9:5337
Sumida, Tomokazu; Lincoln, Matthew R; Ukeje, Chinonso M et al. (2018) Activated ?-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity. Nat Immunol 19:1391-1402
Cremasco, Viviana; Astarita, Jillian L; Grauel, Angelo L et al. (2018) FAP Delineates Heterogeneous and Functionally Divergent Stromal Cells in Immune-Excluded Breast Tumors. Cancer Immunol Res 6:1472-1485
Meyer Zu Horste, Gerd; Przybylski, Dariusz; Schramm, Markus A et al. (2018) Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1. Immunity 48:556-569.e7
Gee, Marvin H; Sibener, Leah V; Birnbaum, Michael E et al. (2018) Stress-testing the relationship between T cell receptor/peptide-MHC affinity and cross-reactivity using peptide velcro. Proc Natl Acad Sci U S A 115:E7369-E7378
Kim, Yong Chan; Zhang, Ai-Hong; Yoon, Jeongheon et al. (2018) Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells. J Autoimmun 92:77-86
Lucca, Liliana E; Hafler, David A (2017) Resisting fatal attraction: a glioma oncometabolite prevents CD8+ T cell recruitment. J Clin Invest 127:1218-1220
Nylander, Alyssa N; Ponath, Gerald D; Axisa, Pierre-Paul et al. (2017) Podoplanin is a negative regulator of Th17 inflammation. JCI Insight 2:
Gierahn, Todd M; Wadsworth 2nd, Marc H; Hughes, Travis K et al. (2017) Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput. Nat Methods 14:395-398

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