Altin, John Andrew
Description
"Helper T cells are required for normal immune function and act by marshalling the activity of other immune cell types. Their biology is dominated by a paradigm in which cells adopt mutually antagonistic functional specializations following their activation. One such specialization, adopted by ""T helper type 2 (Th2)"" cells, is characterized by the production of cytokines including IL-4 that drive a response dominated by the production of IgG and IgE antibodies, and the recruitment of innate...[Show more] inflammatory cells such as mast cells, basophils and eosinophils. A response of this kind mediates protection against extracellular parasites such as helminths, but can also underlie the maladaptive reaction to innocuous non-self antigens that appears central to the etiology of allergy. The possibility for this latter deleterious kind of immune response motivates the work presented in this thesis.
In particular, this thesis addresses the following question: how is the Th2 response regulated? Put another way: what cellular and molecular constraints ensure that Th2 cells do not expand inappropriately? In general, the regulation of helper T cell responses is known to occur by mechanisms that act within effector T cells (""cell-intrinsic"") as well as those that are mediated by other cell types (""cell-extrinsic""). Regulatory mechanisms can also be classified according to whether they operate before a response had developed (""anticipatory""), or emerge only as a consequence of inflammatory activation (""feedback""). Rather than focus a priori on any one of these modes of regulation, or on any particular molecular or cellular pathway, an unbiased experimental approach was adopted here. To this end, inbred mice carrying point mutations induced in a genome-wide fashion by the chemical mutagen ethyl-nitroso urea (ENU) were studied. Since Th2 responses are normally undetectable in naive C57BL/6 mice, genetic variant mice in which such responses were spontaneously evident were of interest, as they were taken to embody a failure of Th2 regulation. The work presented here began with the study of two ENU-generated strains that showed preliminary evidence of Th2 dysregulation in the form of spontaneously elevated serum IgE and dermatitis. Cellular analysis confirmed that that these phenotypes - which result from point mutations in the genes Card11 and Ndfip1 respectively - are associated with striking, spontaneous expansion of Th2 cells.
This thesis describes the study of these mutants to define three new pathways of Th2 regulation: (a) a cell-extrinsic anticipatory pathway mediated by Foxp3+ Tregs and sensitive to inherited partial loss of TCR/CD28-Card11 signaling (chapter 3), (b) a cell-intrinsic feedback pathway regulated by Ndfip1 and the cytokine IL-4 (chapter 4), and (c) a cell-extrinsic feedback pathway mediated by differentiation of effector Th2 cells into a novel cell type, the Th2 inhibitory 'Th2i' cell (chapter 5)."
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