Date of Award
Doctor of Philosophy (PhD)
The generation of an allergic response is particularly perplexing, as the mucosal immune system is exposed to a myriad of antigens on a daily basis, the majority of which do not elicit inflammation. However, for the growing population of patients impacted by allergic diseases, there is a clear breakdown of normal tolerance to innocuous antigens, resulting in symptoms mediated by antigen specific T helper 2 (Th2) cells. In addition to their well-established role in early antiviral immunity via production of type I interferon, plasmacytoid dendritic cells (pDC) have been implicated in the generation of immune tolerance in a variety of settings. Furthermore, evidence suggests that pDC limit chronic type 2 immunopathology that can follow respiratory viral infections. Thus, we hypothesized that pDC may play a role in suppressing the development of Th2 effector cells.
According to previous studies, pDC can have very disparate effects on naïve CD4+ T cell differentiation, with reports showing that pDC prime Th1, Th2, and T regulatory cells. Lacking from our current knowledge is how pDC behave in situ, as many findings rely on data generated in vitro or with adoptive transfer strategies. The current paradigm suggests that differential priming of Th1, Th2 or tolerogenic T cells depends on cell surface and soluble signals that pDCs provide to CD4+ T cells together with peptide-MHCII complex, despite our growing understanding that pDC are poor antigen presenters compared to their conventional DC counterparts. To understand how pDC influence CD4+ T cell polarization in vivo, we used the CLEC4C-DTR transgenic mice, previously generated in our laboratory, which allow for specific and transient depletion of pDC. We found that pDC suppressed a model of Th2-driven cutaneous contact hypersensitivity (CHS) but did not impact a Th1-driven CHS model. PDC depletion skewed CD4+ T cells towards a Th2 phenotype and limited Th1 polarization, through a mechanism independent of the canonical pDC-derived effectors, type I interferon, type III interferon, and IL-12. Instead, pDC shaped T cell polarization indirectly by altering the balance of migratory cDC subsets in the lymph node. pDC-depleted mice had increased Th2/Th17-priming IRF4+ cDC2 and fewer Th1-priming CD103+ IRF8+ cDC1. Single cell RNA-sequencing analysis also revealed that pDC-depleted mice had an expansion of non-canonical CX3CR1+ DC, which shared features with both pDC and DC2. Our results suggest a novel model in which pDC can influence T cell polarization by controlling the balance of cDC subsets within the lymph node during T cell priming. This novel function of pDC undoubtedly contributes to the ability of pDC to suppress allergic pathology and defines new therapeutic approaches to help patients afflicted with allergic and atopic disease.
Chair and Committee
Kenneth M. Murphy, Paul M. Allen, Brian T. Edelson, Brian S. Kim,
Miller, Hannah Leigh, "A Novel Function of Plasmacytoid Dendritic Cells in Regulating Type 2 Immune Responses" (2021). Arts & Sciences Electronic Theses and Dissertations. 2445.