Lymphocytes respond to antigens with a series of events that constitute the T cell activation process. T cell activation is necessary and beneficial when the antigen is a pathogen or a cancer cell, but it becomes undesirable when the immune system identifies components of the body's own cells as foreign. This aberrant response occurs in autoimmune diseases. Thus studying the activation process of normal and autoimmune T cells is of primary importance. T cell activation is initiated by contact of the T cell with the antigen presenting cell (APC) and formation of the immunological synapse (IS). The IS is a highly organized signaling zone that forms at the T/APC interface and is needed for full development of the activation response. Although various aspects of the process of IS formation have been thoroughly investigated, the underlying membrane ionic events are poorly understood. Kv1.3 potassium channels are expressed in T cells where they compartmentalize together with the T cell receptor complex and various signaling molecules at the IS. Kv1.3 channels play an important role during T cell activation as they regulate the Ca2+ influx necessary for downstream functional events. Indeed, inhibition of these channels terminates the immune response and therefore Kv1.3 blockers are under development as novel immunosuppressive agents. Despite the significance of these channels, the functional consequences of their compartmentalization in the IS of T cells are yet to be determined. Preliminary data from our laboratory suggest that Kv1.3 location within the IS is necessary to regulate the channel function and alterations in Kv1.3 channel localization in the IS have been observed in the autoimmune disease SLE. In this application we will be testing the hypothesis that Kv1.3 channels'recruitment in the immunological synapse and their specific location within this structure is necessary for regulation of the channel activity and consequently it influences the outcome of T cell activation. Specifically we will engineer artificial APC-like surfaces allowing targeted sequestration of Kv1.3 proteins in a predetermined location within the IS and simultaneous measurement of downstream functional events. These studies will establish the feasibility of engineered protein surfaces for studying ion channel compartmentalization in the IS, specifically addressing the question of how the position of ion channels in the IS determines the outcome of T cell/APC interactions. Furthermore, these studies will enable understanding of the implications that abnormalities in ion channel recruitment into the IS have on overall T cell function in pathological conditions.

Public Health Relevance

Lymphocytes function, and also therefore malfunction, is in part controlled by Kv1.3 channels in the cell membrane. We are interested in studying details of how the location of Kv1.3 channels in the contact point between T cells and antigen presenting cells affects the channels'function. To do this we propose a novel method combining nanotechnology and artificial antigen presenting cell-like surfaces.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Nanotechnology Study Section (NANO)
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Mallia, Conrad M
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University of Cincinnati
Internal Medicine/Medicine
Schools of Medicine
United States
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