Program Director/Principal investigator (Last, First, Middle): Dustln, Michael, LotanPROJECT SUMMARY (See instmctions):The long-tenn goal of our work is to determine the mechanisms by which conventional and regulatory Tlymphocytes are activated by very small numbers of MHC-peptide complexes on the surface of antigenpresenting cells. This sensitivity determines the threshold for activation of mature T cells and thus may playan important role in tolerance and immunity. Work from our lab and others has shown that antigenreceptors, adhesion molecules and cytoskeletal dynamics collaborate to form a highly orderedimmunological synapse, which sustains signaling by unknown mechanisms. We have observed that theorganization and dynamics of T cell antigen receptors in the immunological synapse depends upon whichadhesion systems are engaged. A prominent feature of the immunological synapse fomned with differentadhesion systems is small TOR clusters in the periphery of the contact area.
In Aim 1 we will test the role ofperipheral TOR clusters in sustained signaling and T cell activation. We will identify an optimal combinationof iCAM-1, CD48, CD80 and MHC-peptide complexes in supported planar bilayers and will compare this towhat is observed with a professional antigen presenting cell type, the dendritic cell (DC). Co-receptormolecule CD4 plays an important role in setting T cell sensitivity to antigen.
In Aim 2 we will test theimportance of different putative interactions of CCM with MHC class II, Lck, membrane domains, the TCRand itself in T cell sensitivity to antigen. The actin cytoskeieton has an essential role in T cell responses toantigen. Cofilin, cortactin and Arp2/3 are associated with dynamic lamellipodia, which are sites of sensitivesignal initiation. The lamella is directly behind the lamellipodium and contains actin filaments that arestabilized by tropomyosin and the actin-integrin adapter protein talin.
In Aim 3 we will investigate the actinbased structures in immunological synapses formed with different adhesion systems. Then we will use RNAinterference and overexpression studies to manipulate the expression of actin regulators. In the context ofregulatory T cells, we will study the role of intermediate filament proteins. These studies will lead to agreater understanding of sensitivity to self and foreign antigen in immune response and regulation.

Public Health Relevance

The ability of conventional T lymphocytes to respond to foreign antigens with high sensitivity is essential tovaccination, whereas the ability of regulatory T cells to sensitively respond to self antigens presentsautoimmunity. Understanding the fundamental structures that mediate sensitive antigen recognition maylead to better immunotherapies for cancer and infectious diseases and treatments for autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AI043542-14
Application #
8124309
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mallia, Conrad M
Project Start
1999-03-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
14
Fiscal Year
2012
Total Cost
$373,644
Indirect Cost
$152,553
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Lin, Jiqiang; Yang, Lu; Silva, Hernandez Moura et al. (2016) Increased generation of Foxp3(+) regulatory T cells by manipulating antigen presentation in the thymus. Nat Commun 7:10562
Saha, Asim; O'Connor, Roddy S; Thangavelu, Govindarajan et al. (2016) Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. J Clin Invest 126:2642-60
Schmid, Eva M; Bakalar, Matthew H; Choudhuri, Kaushik et al. (2016) Size-dependent protein segregation at membrane interfaces. Nat Phys 12:704-711
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
Kumari, Sudha; Depoil, David; Martinelli, Roberta et al. (2015) Actin foci facilitate activation of the phospholipase C-γ in primary T lymphocytes via the WASP pathway. Elife 4:
Biswas, Kabir H; Hartman, Kevin L; Yu, Cheng-han et al. (2015) E-cadherin junction formation involves an active kinetic nucleation process. Proc Natl Acad Sci U S A 112:10932-7
Tabdanov, Erdem; Gondarenko, Sasha; Kumari, Sudha et al. (2015) Micropatterning of TCR and LFA-1 ligands reveals complementary effects on cytoskeleton mechanics in T cells. Integr Biol (Camb) 7:1272-84
Thauland, Timothy J; Koguchi, Yoshinobu; Dustin, Michael L et al. (2014) CD28-CD80 interactions control regulatory T cell motility and immunological synapse formation. J Immunol 193:5894-903
Dustin, Michael L; Davis, Simon J (2014) TCR signaling: the barrier within. Nat Immunol 15:136-7
Pollitt, Alice Y; Poulter, Natalie S; Gitz, Eelo et al. (2014) Syk and Src family kinases regulate C-type lectin receptor 2 (CLEC-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells. J Biol Chem 289:35695-710

Showing the most recent 10 out of 37 publications