Antigen Presentation in the CNS by Myeloid Dendritic Cells Drives Progression of Relapsing Experimental Autoimmune Encephalomyelitis

Abstract

Chronic progression of relapsing experimental autoimmune encephalomyelitis (R-EAE), a mouse model of multiple sclerosis (MS), is dependent on the activation of T cells to endogenous myelin epitopes, that is, epitope spreading. This review focuses on the cellular and molecular mechanisms underlying the process of epitope spreading. Surprisingly, activation of naïve T cells to endogenous myelin epitopes in SJL mice undergoing R-EAE occurs directly in the central nervous system (CNS), a site generally perceived to be immunologically privileged. Determination of the antigen presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with established R-EAE shows that peripherally derived CD11b(+)CD11c(+)CD45(hi) myeloid dendritic cells (mDCs) most efficiently present endogenous myelin antigens to activate both preactivated effector myelin-specific T cells and naïve T cells. The mDCs, which drive epitope spreading, preferentially polarize pathogenic Th17 responses correlating with their enhanced expression of TGF-beta1, IL-6, and IL-23. Both B220(+)CD11c(+) plasmacytoid (pDCs) and CD8alpha(+)CD11c(+) (CD8 DCs) were superior to CD11b(+)CD11c(-)CD45(hi) macrophages, but less efficient than mDCs at presenting endogenous peptide to induce Th17 cells. In contrast, CNS-resident CD11b(+)CD11c(-)CD45(low) microglia purified from the inflamed CNS were found to be largely incapable of activating either naïve or effector T cells.

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

“…These professional APCs have been suggested to participate in restimulation of myelin-specific CD4 + T cells in the CNS (5,7,39,40). The identification of equal numbers of DCs in the CCR4 −/− and WT CNS at the onset of disease suggested no major differences in CNS migration, but cannot fully exclude that migratory deficits of CCR4 −/− DCs occur at a later time point during disease development.…”

“…In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4)(5)(6)(7)(8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.…”

Experimental Autoimmune Encephalomyelitis (EAE) Induced by Antigen Pulsed Dendritic Cells in the C57BL/6 Mouse: Influence of Injection Route

“…Indeed three distinct DCs populations are found to be present in the CNS during the clinical stage of EAE: myeloid DCs, plasmacytoid DCs and lymphoid DCs [3]. Myeloid DCs are the most abundant at the acute phase of EAE (approximately 11% of the CNS mononuclear cells) [40]. Although CNS DCs expressed similar profiles of accessory molecules, myeloid DCs were distinct in their ability to activate both proliferation and differentiation of naïve CD4 + T cells to produce IL-17 both in vitro and in the inflamed CNS [3].…”

Central histamine H3receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

“…6). This may be directly at the level of the infiltrating T cells or indirectly through CNS resident antigenpresenting cells, such as dendritic cells, which have been proposed to be critical for the development and perpetuation of autoimmunity (55). Pathogenic T cells likely interact with ''dendritic cell-like microglia'' (56) and/or radiation-sensitive CD11cϩ dendritic cells (57,58) to enter the CNS.…”