Chronic progression of two T cell-mediated central nervous system (CNS) demyelinating models of multiple sclerosis, relapsing EAE (R-EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is dependent on the activation of T cells to endogenous myelin epitopes (epitope spreading). Using transfer of carboxyfluorescein succinyl ester (CFSE)-labeled T-cell receptor (TCR)-transgenic T cells and mixed bone marrow chimeras, we show that activation of naive proteolipid protein (PLP)139-151-specific T cells in SJL mice undergoing PLP178-191-induced R-EAE or TMEV-IDD occurs directly in the CNS and not in the cervical lymph nodes or other peripheral lymphoid organs. Examination of the antigen-presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with PLP178-191-induced R-EAE shows that only F4/80-CD11c+CD45hi dendritic cells (DCs) efficiently present endogenous antigen to activate naive PLP139-151-specific T cells in vitro. In contrast, DCs as well as F4/80+CD45hi macrophages and F4/80+CD45lo microglia activate a PLP139-151-specific helper T cell line. The data suggest that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.

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.

In response to ER stress, the pancreatic endoplasmic reticulum kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating the α subunit of eukaryotic translation initiation factor 2 (eIF2α). IFN-γ, which activates the ER stress response in oligodendrocytes, is believed to play a critical role in the immune-mediated CNS disorder multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Here we report that CNS delivery of IFN-γ before EAE onset ameliorated the disease course and prevented demyelination, axonal damage, and oligodendrocyte loss. The beneficial effects of IFN-γ were accompanied by PERK activation in oligodendrocytes and were abrogated in PERK-deficient animals. Our results indicate that IFN-γ activation of PERK in mature oligodendrocytes attenuates EAE severity and suggest that therapeutic approaches to activate the ISR could prove beneficial in MS.

CD4 ؉ CD25 ؉ Foxp3 ؉ regulatory T cells (T regs) are important for preventing autoimmune diabetes and are either thymic-derived (natural) or differentiated in the periphery outside the thymus (induced). Here we show that ␤-cell peptide-pulsed dendritic cells (DCs) from nonobese diabetic (NOD) mice can effectively induce CD4 ؉ CD25 ؉ Foxp3 ؉ T cells from naïve islet-specific CD4 ؉ CD25 ؊ T cells in the presence of TGF-␤1. These induced, antigen-specific T regs maintain high levels of clonotype-specific T cell receptor expression and exert islet-specific suppression in vitro. When cotransferred with diabetogenic cells into NOD scid recipients, T regs induced with DCs and TGF-␤1 prevent the development of diabetes. Furthermore, in overtly NOD mice, these cells are able to significantly protect syngeneic islet grafts from established destructive autoimmunity. These results indicate a role for DCs in the induction of antigen-specific CD4 ؉ CD25 ؉ Foxp3 ؉ T cells that can inhibit fully developed autoimmunity in a nonlymphopoenic host, providing an important potential strategy for immunotherapy in patients with autoimmune diabetes.antigen-presenting cells ͉ autoimmunity ͉ type 1 diabetes ͉ nonobese diabetic (NOD) mice T he nonobese diabetic (NOD) mouse models the pathogenesis of human type 1 diabetes and allows the study of potential therapeutics (1). In NOD mice, the thymic-derived CD4 ϩ CD25 ϩ regulatory T cells (T regs) expressing the transcription factor Foxp3 suppress autoimmunity and delay the development of diabetes (2). Considerable effort has focused on expanding the small numbers of these so-called ''natural'' CD4 ϩ CD25 ϩ T regs in the NOD and other models (3-6). Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that can effectively expand and sustain antigen-specific CD4 ϩ CD25 ϩ T regs (3, 4). However, in humans, only the infrequent cells with high CD25 expression have regulatory function (7). Alternatively, the more abundant CD4 ϩ CD25 Ϫ T cells can be differentiated into CD4 ϩ CD25 ϩ T regs that express Foxp3 by stimulation with mitogenic antibodies in the presence of TGF-␤1, although it is not known whether these induced cells are functionally identical to T regs that develop in the thymus (8). Such ''induced T regs'' with islet specificity can prevent diabetes in lymphopoenic models (9), but their ability to induce tolerance at late pathogenic stages of autoimmunity, such as in already-diabetic NOD mice, has not been fully addressed.A separate issue that remains to be addressed is the requirement for APCs in the induction of T regs with TGF-␤1. The use of DCs instead of mitogenic stimuli to differentiate T regs de novo from CD4 ϩ CD25 Ϫ T cells has numerous potential advantages, including selection and maintenance of antigen specificity (10, 11); provision of paracrine TGF-␤1 (12-14), which is known to play an important role in T reg homeostasis by its ability to induce Foxp3 (8, 15); and/or provision of costimulatory signals such as CD80/86 for CTLA-4 ligation, which is necessary f...

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