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.
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.
|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|
|Choudhuri, Kaushik; Llodrá, 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|
|Céspedes, Pablo F; Bueno, Susan M; Ramírez, Bruno A et al. (2014) Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. Proc Natl Acad Sci U S A 111:E3214-23|
|Cordoba, Shaun-Paul; Choudhuri, Kaushik; Zhang, Hao et al. (2013) The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor. Blood 121:4295-302|
|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|
|Zanin-Zhorov, Alexandra; Lin, Jiqiang; Scher, Jose et al. (2012) Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function. Proc Natl Acad Sci U S A 109:1625-30|
|Dustin, Michael L; Groves, Jay T (2012) Receptor signaling clusters in the immune synapse. Annu Rev Biophys 41:543-56|
|Manz, Boryana N; Jackson, Bryan L; Petit, Rebecca S et al. (2011) T-cell triggering thresholds are modulated by the number of antigen within individual T-cell receptor clusters. Proc Natl Acad Sci U S A 108:9089-94|
|Tang, Wei; Lu, Yi; Tian, Qing-Yun et al. (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332:478-84|
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