Cytotoxic T cells have a critical role in eliminating intracellular pathogens and tumors. They arise when naive CD8 T cells are exposed to mature dendritic cells (DCs) that present an activating antigen (Ag). Upon priming by DCs, naive T cells differentiate into mostly short-lived cytotoxic effector cells and relatively few long-lived memory cells. Several memory cell subsets with distinct tissue tropism exist, of which the central memory cells are particularly important for sustained immune protection. We have developed in vitro methods to generate homogenous antigen-specific effector and central memory cell populations using T cells from newly constructed transgenic mice in which each subset expresses distinct genetically encoded fluorescent tags. These cells will be studied in homing experiments and by intravital microscopy to investigate the traffic signals that guide them to normal and inflamed tissues.
Aim 1 is based on the hypothesis that upon antigen stimulation CD8 T cells acquire the capacity to migrate to certain non-lymphoid tissues, especially sites of inflammation. We will characterize these default changes in CD8 T cell trafficking that are evoked by TCR stimulation and cytokines without tissue-specific signals. We will dissect the molecular mechanisms by which in vitro generated effector and central memory cells migrate to normal and inflamed tissues (subaim 1.1) and examine the role of the lipid chemo attractant leukotriene B4 and its receptor BLT1 (subaim 1.2).
Sub aim 1. 3 will determine where and when activated T cells acquire effector functions in vivo. In addition to the antigenic stimulus, the route of immunization also influences memory cell migration. We have discovered that lymphoid organ-specific DCs instruct T cells how to migrate to those tissues that are most likely to contain their cognate Ag.
Aim 2 will explore how a particular tissue context modulates T cell differentiation induced by DCs and investigate the mechanisms of DC-mediated tissue-specific imprinting. We will ask how DCs from Peyer's patches induce effector cell migration to the small intestine (subaim 2.1) and whether DCs from cutaneous lymph nodes target effector cells to the skin (subaim 2.2). In subaim 2.3 we will dissect the mechanisms that allow skin- and gut-tropic effector cells to migrate into uninflamed tissues and determine how inflammation affects tissue-selectivity.
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