Modulation of T Cell Function by Patterning of Costimulatory Ligands

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DESCRIPTION (provided by applicant): T cell activation is mediated by a dynamic interface between T cells and antigen presenting cells, termed the immunological synapse. The long-term goal of these studies is to understand how the organization of molecules within the immunological synapse drives cell function as well as the molecular mechanisms that mediate such processes. Preliminary studies demonstrate that micrometer-scale segregation of T cell receptor and CD28 costimulatory ligands enhances IL2 production by na¿ve murine CD4+ T cells. The proposed studies seek to identify key points of modulation in the cell signaling pathways that lead from receptor engagement to IL2 secretion, as a survey for potential mechanisms by which cells recognize and respond to the segregation of costimulatory signals. The proposed studies will use two approaches for defining multicomponent surfaces containing ligands to TCR and CD28. First, microcontact printing will be used to define colocalized and segregated patterns of activating antibodies to TCR (CD3) and CD28. Second, membrane microfluidics will be used to create aligned regions of supported lipid bilayer to which I-Ek and CD80 (natural ligands to TCR and CD28, respectively) are tethered. Immunological and live imaging approaches will be used to identify differences in signaling and migratory behavior that are induced by segregation of ligands. Subsequent studies will focus on the specific biophysical presentation of proteins that are identified, in an effort to identify the molecular mechanisms that are being invoked by signal segregation. Successful completion of these studies will provide new insight into mechanisms by which cells integrate multiple cues of the extracellular environment, an ability that impacts on understanding how cells organize into a variety of physiologically important systems. Moreover, the knowledge gained here may have application in improving the ex vivo expansion of T cell populations, which is currently carried out using beads and other structures that are simply coated with activating antibodies; understanding how patterning of these signals and modulate T cell function is immediately applicable to improving these systems.7. Project Narrative Proper function of the immune system has strong impacts on a variety of diseases as well as therapeutic potential. The proposed study seeks to understand how changing the distribution of biomolecules presented to T cells influences their development into fully activated cells, a phenomenon observed in many T cell interactions. Successful completion of these studies will lead to a better understanding of immune system function and can lead to improved devices and methods for tailoring immune responses.