Elucidation of Ikaros function in peripheral T cell responses in vivo

Boston University Medical Campus, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Regulation of appropriate antigen-specific immune responses is crucial for human health. An immune system that does not function properly can result in immunodeficiency, whereas one that mounts inappropriate responses can result in autoimmune and allergic diseases. CD4 T helper (Th) cells are organizers of the immune response, directing other immune cells to initiate and maintain effective humoral and cellular immunity. Naive CD4 T cells are thought to have uniform differentiation potential and it is the nature of a pathogenic assault that elicits signals to drive acquisition of specific Th cell phenotypes tailored to combat the infection. After the danger has passed, a small subset of CD4 Th cells survive as memory cells to provide the adaptive immune response its hallmark ability to respond more quickly and robustly in a recall response, a concept that underlies vaccine efficacy. Adding complexity to this scenario, although it was initially believed that attainment ofa Th cell phenotype represented an end-stage differentiation event, it is now becoming apparent that this is not always the case. Many studies now suggest that Th cells can be reprogrammed to an alternative Th cell lineage. It is easy to postulate that this plasticity is advantageous in hat it would allow Th cells to revise their effector functions based on external cues in the immediate inflammatory microenvironment. Elicitation of primary Th effector functions, formation of CD4 T cell memory and alteration of Th cell phenotype require induction of novel programs of gene expression, likely through epigenetic re-programming. Defining the nuclear regulatory factors that control these transitions will lead to a better understanding of how they are regulated and provide new targets for interventions to halt harmful and boost helpful immune responses. The protein Ikaros is an attractive candidate as it associates with chromatin remodeling complexes and histone modifying enzymes in T cells. T cells derived from genetically engineered Ikaros null mice display alterations in Th cell development and response to T cell receptor stimulation, but these studies have only been performed ex vivo as the complex phenotype of Ikaros null mice prohibits in vivo analyses of T cell function. In addition, since Ikaros is expressed from the level of the hematopoietic stem cell and lack of Ikaros affects thymic T cell development, the legitimacy of comparing function of mature Ikaros null T cells to their wild-type counterparts has been questioned. We have now generated an Ikaros conditional knockout mouse that can be used to assess the role of Ikaros in mediating T cell immunity in vivo. Here, we propose to use this model to examine the T-cell intrinsic role of Ikaros in Th cell development, CD4 T cell memory, T cell dependent B cell responses and Th cell stability/plasticity. These studies will define at which stages Ikaros functions in CD4 T cells during the course of an immune response, a goal that has been out of reach using current model systems, providing novel insight that we hope will translate into new areas for disease intervention.