33D1+ Dendritic Cells in Tolerance and Immunity
STOLLEY, James M.
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CD4+ Foxp3+ regulatory T cells (Tr cells) are potent anti-inflammatory cells which naturally suppress autoimmune disease by tempering immune responses to self- and foreign-antigens. Given their integral role in the maintenance of self-tolerance, the manipulation of Tr cell abundance and/or function has tremendous implications for the treatment of a spectrum of diseases including autoimmunity, graft rejection, and cancer. Although once thought to represent a uniform group of immuoregulatory cells, work from our lab and others over the past several years has demonstrated considerable phenotypic and functional heterogeneity exist amongst Tr cells. Broadly, Tr cells can be subsetted based on their localization within secondary-lymphoid (SLO) and non-lymphoid tissues where they exhibit a unique dependence on IL-2 signaling and TCR/co-stimulatory receptor activation for their homeostatic maintenance and function, respectively. Loss of either of these distinct Tr cell subsets is sufficient to invoke lethal autoimmunity. However, Tr cells are incapable of IL-2 production due to transcriptional repression at the IL-2 locus by Foxp3 and are therefore dependent on paracrine sources of IL-2 downstream of cellular and molecular interactions which are largely Tr cell-extrinsic. The results presented in this dissertation comprehensively identify the components of the circuit sustaining IL-2-dependent Tr cells in the spleen. Here we demonstrate the presentation of MHCII-restricted auto-antigens by CD80/86-bearing 33D1+ CD11bint DCs to self-reactive CD4+ T cells within T cell zones of the spfleen synchronizes the frequency and function of IL-2-dependent Tr cells, preventing spontaneous autoimmunity. Furthermore, the amount of homeostatic IL-2 generated through this circuit is limiting for Tr cells and subtle perturbations in its availability can enhance immune activation directly through its impact on IL-2-dependent Tr cells. Therefore, altering the IL-2 reservoir, either directly or through the manipulation of 33D1+ CD11bint DCs or additional molecules which stimulate its production, could be therapeutically beneficial in augmenting immune responses naturally constrained by Tr cells. Our findings also help reconcile the apparent paradox of lethal autoimmunity which develops in mice constitutively lacking DCs, which we posit results from the selective loss of IL-2-dependent Tr cells no longer supported by IL-2 release downstream of 33D1+ CD11bint DCs. Moreover we report DC-intrinsic CD4 expression, historically used to delineate DCs in the spleen but functionally undefined, is dynamically regulated on 33D1+ DCs in a cell intrinsic manner and augments the function of 33D1+ DCs in part through its ability to influence IL-2 production from CD4+ T cells in response to complex antigens. Thus, 33D1+ DCs are integral for sustaining self-tolerance through their indirect maintenance of Tr cells, and modulate CD4 expression to potentially regulate the magnitude and/or duration of an immune response.
- Immunology