A 33D1+ Dendritic Cell/Autoreactive CD4+ T Cell Circuit Maintains IL-2–Dependent Regulatory T Cells in the Spleen

Abstract

Phenotypically and functionally diverse regulatory T cell (Tr cell) subsets populate lymphoid and non-lymphoid tissues where their maintenance and function are governed by unique homeostatic signals. Whereas Tr cells resident in non-lymphoid tissues depend on continual TCR signaling for their survival and function, phenotypically naïve Tr cells occupying secondary lymphoid organs (SLOs) are largely supported by paracrine Il-2 signaling. Crucially, the absence of either of these distinct Tr cell subsets results in pathogenic autoimmunity, underscoring their non-redundant roles in the preservation of self-tolerance. However, the cellular and molecular factors precipitating Il-2 release and subsequent maintenance of SLO-resident Tr cells are still poorly understood. Here we report that Il-2-dependent Tr cells in the spleen compete for a limiting supply of paracrine Il-2 generated by auto-reactive CD4+ T cells in response to MHCII-restricted auto-antigen activation by 33D1+ CD11bint DCs. Manipulating this cellular circuit culminating in Il-2 production could have clinical benefits in settings where diminished Tr cell abundance is desired.

Treg cells maintain selective access to IL-2 and immune homeostasis despite substantially reduced CD25 function

“…3A). This is consistent with a central role for cDC2 in interaction with Treg cells [9]. Along with the increase in activated DCs, the anti-IL-2 treated mice also showed enhanced proliferation of the Foxp3 -CD44 + CD4 + and CD44 + CD62L + CD8 + Teff cell populations as assessed by Ki67 staining (Fig.…”

“…Whereas neutralization of IL-2 blocked all pSTAT5 as expected, surprisingly Treg cells from animals treated with PC61 N297Q maintained normal levels of pSTAT5, and even treatment with PC61 2a had only a modest impact of the frequency of pSTAT5 + Treg cells ( Fig 4A). The pSTAT5 staining we observed in the treated animals does not simply reflect prolonged IL-2 signaling that occurred prior to treatment initiation, as we have previously shown that injection of IL-2 antibodies as little as 30 minutes prior to sacrifice ameliorates all detectable pSTAT5 in Treg cells [9]. Treatment with PC61 N297Q or PC61 2a also did not redirect IL-2 to effector cells, as the gMFI of pSTAT5 in both NK cells and CD44 + CD62L + CD8 + Teff was not increased by any of the treatments ( Fig S2A).…”

“…We hypothesized that impaired Treg cell function with IL-2 neutralization led to the increased costimulatory molecule expression on cDC2s, which in turn allowed these DCs to more potently activate naïve autoreactive T cells. To test this, we used mice expressing a soluble form of ovalbumin (sOVA) that is efficiently processed and presented on the surface of splenic cDC2s [9,36]. sOVA mice were treated with PBS, PC61 N297Q , or anti-IL-2.…”

“…This is most important in the secondary lymphoid organs (SLOs), where prosurvival signals downstream of IL-2 signaling maintain Treg cells [4,5]. Notably, Treg cells cannot make their own IL-2 [6, 7] and depend on IL-2 produced mainly from autoreactive CD4 + Teff cells [8,9]. In this way, Teff and Treg cell populations are dynamically linked and reciprocally control each other to maintain immune homeostasis [10].When the IL-2-dependent balance of Treg and Teff cells is disrupted, autoimmunity and inflammation can occur.…”

Immune Cell Responses and Cytokine Profile in Intestines of Mice Infected with Trichinella spiralis

“…33D1+ DCs not only induced Th0 cells to Th2 cells, but also influenced the frequency and function of Treg cells. The frequency and function of IL-2–dependent Treg cells depends on the presentation of MHC II–restricted autoantigens to self-reactive CD4+ T cells via 33D1+ DCs ( Stolley and Campbell, 2016 ).…”