Immunotherapy with Costimulatory Dendritic Cells To Control Autoimmune Inflammation

Abstract

Costimulation-deficient dendritic cells (DCs) prevent autoimmune disease in mouse models. However, autoimmune-prone mice and humans fail to control expansion of peripheral autoreactive effector memory T cells (TEMs), which resist immunoregulation by costimulation-deficient DCs. In contrast, activation of DC costimulation may be coupled with regulatory capacity. To test whether costimulatory DCs control TEMs and attenuate established autoimmune disease, we used RelB-deficient mice, which have multiorgan inflammation, expanded peripheral autoreactive TEMs, and dysfunctional Foxp3+ regulatory T cells (Tregs) cells and conventional DCs. TEMs were regulated by Foxp3+ Tregs when costimulated by CD3/CD28-coated beads or wild-type DCs but not DCs deficient in RelB or CD80/CD86. After transfer, RelB and CD80/CD86-sufficient DCs restored tolerance and achieved a long-term cure of autoimmune disease through costimulation of TEM and Foxp3+ Treg IFN-γ production, as well as induction of IDO by host APCs. IDO was required for regulation of TEMs and suppression of organ inflammation. Our data challenge the paradigm that costimulation-deficient DCs are required to regulate established autoimmune disease to avoid TEM activation and demonstrate cooperative cross-talk between costimulatory DCs, IFN-γ, and IDO-dependent immune regulation. IFN-γ and IDO activity may be good surrogate biomarkers measured against clinical efficacy in trials of autoimmune disease immunoregulation.

Comparison of the innate immune responses of porcine monocyte-derived dendritic cells and splenic dendritic cells stimulated with LPS

“…In addition, the expression of CD40 on DCs is important for T-cell priming and T-cell-mediated effector function. 32 LPS-stimulated human or mice moDCs display a strong expression of the maturation markers CD40 and CD86, 31,33 which is in agreement with this study. We identified that the costimulatory molecules were up-regulated in both moDCs and SDCs, whereas moDCs were induced to be more mature than SDCs following LPS stimulation.…”

“…30 It is well-described that CD80/86 through CD28 increase pro-inflammatory cytokine production in T-cells. 31 CD86 was found to be up-regulated on the cell surface of DCs, suggesting that it interacted with CD28, thereby promoting T-cell activation and maturation. In addition, the expression of CD40 on DCs is important for T-cell priming and T-cell-mediated effector function.…”

Layers of dendritic cell-mediated T cell tolerance, their regulation and the prevention of autoimmunity

“…The underlying mechanisms remain to be explored. Foxp3 + Treg homeostasis is likely enforced by inflammation which e.g., causes the increased expression of MHC-class-II, CD80, CD86, and IL-2 (Oldenhove et al, 2003; Yamazaki et al, 2003; Banerjee et al, 2006; O'Sullivan et al, 2011). In summary, DCs critically regulate the homeostasis and activation state of Foxp3 + Tregs.…”

The thymic medulla: who needs it?

“…1 Although normal T reg cell numbers were observed in the periphery, this restoration is likely due to the potent homeostatic mechanisms that normally restore T reg cell deficits. 6 Collectively, these findings challenge the notion that conventional thymocyte maturation requires the thymic medulla, but what about immunological tolerance? Young Foxn1 Cre Traf6 fl/fl mice initially appeared normal, but then lost weight and their health deteriorated after 6 months of age.…”

“…The transcriptional activity of RelB in immature DCs is low, and indeed Treg are increased in RelB-deficient mice and induced by transfer of RelB-deficient DCs to wild-type hosts. 4,6 Far from a state of immunosuppression though, naive T cells in the resting state require persistent low-level MHC peptide-mediated signalling for their survival and this constitutive signalling by resting DCs promotes T-cell sensitivity to immunogenic antigen presentation. 7 Second, peripheral tolerance must regulate the immune response to a variety of inflammatory signals, including pathogen-derived endotoxin, endogenous cytokines, proinflammatory toxins and tumour environment and damage-associated molecules.…”