CNS myeloid DCs presenting endogenous myelin peptides 'preferentially' polarize CD4+ TH-17 cells in relapsing EAE

Abstract

Peripherally derived CD11b(+) myeloid dendritic cells (mDCs), plasmacytoid DCs, CD8alpha(+) DCs and macrophages accumulate in the central nervous system during relapsing experimental autoimmune encephalomyelitis (EAE). During acute relapsing EAE induced by a proteolipid protein peptide of amino acids 178-191, transgenic T cells (139TCR cells) specific for the relapse epitope consisting of proteolipid protein peptide amino acids 139-151 clustered with mDCs in the central nervous system, were activated and differentiated into T helper cells producing interleukin 17 (T(H)-17 cells). CNS mDCs presented endogenously acquired peptide, driving the proliferation of and production of interleukin 17 by naive 139TCR cells in vitro and in vivo. The mDCs uniquely biased T(H)-17 and not T(H)1 differentiation, correlating with their enhanced expression of transforming growth factor-beta1 and interleukins 6 and 23. Plasmacytoid DCs and CD8alpha(+) DCs were superior to macrophages but were much less efficient than mDCs in presenting endogenous peptide to induce T(H)-17 cells. Our findings indicate a critical function for CNS mDCs in driving relapses in relapsing EAE.

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

“…It is not known whether the arrival of T cells or peripheral APCs in the CNS or another process altogether is the initiating event for diseases such as PND. Interestingly, Bailey and colleagues have shown that CNS myeloid DCs present endogenous peptide to T cells in the brain to drive EAE relapses in mouse models 39. The mechanism of immunosuppression and CXCL10 reduction in PND patients treated with FK506 may include decreased recruitment of T cells and/or APC from the periphery to the CNS, or interruption of the interaction of these two cell types or their intracellular signaling.…”

An epitope from Acanthamoeba castellanii that cross-react with proteolipid protein 139-151-reactive T cells induces autoimmune encephalomyelitis in SJL mice

“…Myelin antigens such as MBP and PLP can be expressed in thymus and peripheral lymphoid tissues and aberrant expression of PLP transcripts importantly DM20, an isoform of PLP lacking PLP 139-151 motif contribute to the endogenous generation of PLP 139-151 reactive T cells by escaping central tolerance (Anderson et al, 2000;Klein et al, 2000;Voskuhl, 1998). Furthermore, healthy humans including MS patients react to MBP or PLP suggestive of the existence of endogenous myelin reactive T cell repertoires and the resident dendritic cells and microglia can present antigens locally within CNS (Bailey et al, 2007;Pette et al, 1990;Wucherpfennig and Strominger, 1995). Therefore, it is likely that during the course of natural infection with ACA, the resident Ag-presenting cells can present a peptide encompassing 83-95, stimulate the expansion of PLP 139-151-reactive CD4 T cells by molecular mimicry, and induce autoimmunity in the CNS.…”

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

“…Helper CD4 + T cells that are characterized by the production of IL-17 are commonly called Th17 cells [1][2][3][4][5][6]. Th17 cells have features that are distinct from those of both Th1 and Th2 lineages.…”

“…Th17 cells have features that are distinct from those of both Th1 and Th2 lineages. For example, TGF-b and IL-6 are required for the generation of Th17 cells, and IL-23 supports the survival and expansion of these cells [1][2][3][4][5][6][7][8]. Recent data also suggest that IL-6 and TGF-b drive initial lineage commitment of Th17 cells, whereas IL-23 mediates the full acquisition of pathogenic function of Th17 cells [9].…”

“…Recent data also suggest that IL-6 and TGF-b drive initial lineage commitment of Th17 cells, whereas IL-23 mediates the full acquisition of pathogenic function of Th17 cells [9]. Studies in several experimental models have indicated that IL-17 is a major mediator of tissue inflammation and autoimmune disease [4][5][6], but the cellular source of the cytokines and chemokines required for Th17 development and recruitment during initiation of autoimmunity have not been investigated as yet.…”