De Novo Central Nervous System Processing of Myelin Antigen Is Required for the Initiation of Experimental Autoimmune Encephalomyelitis

Self Cite

699

506

Autoreactive CD4+ T cells exist in normal individuals and retain the capacity to initiate autoimmune disease. The current study investigates the role of CD4+CD25+ T-regulatory (TR) cells during autoimmune disease using the CD4+ T cell-dependent myelin oligodendrocyte glycoprotein (MOG)-specific experimental autoimmune encephalomyelitis model of multiple sclerosis. In vitro, TR cells effectively inhibited both the proliferation of and cytokine production by MOG35–55-specific Th1 cells. In vivo, adoptive transfer of TR cells conferred significant protection from clinical experimental autoimmune encephalomyelitis which was associated with normal activation of autoreactive Th1 cells, but an increased frequency of MOG35–55-specific Th2 cells and decreased CNS infiltration. Lastly, transferred TR cells displayed an enhanced ability to traffic to the peripheral lymph nodes and expressed increased levels of the adhesion molecules ICAM-1 and P-selectin that may promote functional interactions with target T cells. Collectively, these findings suggest that TR cells contribute notably to the endogenous mechanisms that regulate actively induced autoimmune disease.

Section: Discussionmentioning

confidence: 79%

“…CNS immunohistochemistry was performed as previously described (11). For immunofluorescence, single-cell suspensions were washed and incubated with fluorescently tagged Abs directed against a panel of cell surface markers (BD PharMingen, San Diego, CA).…”

Section: Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

Cutting Edge: CD4+CD25+ Regulatory T Cells Suppress Antigen-Specific Autoreactive Immune Responses and Central Nervous System Inflammation During Active Experimental Autoimmune Encephalomyelitis

Kohm

Carpentier

Anger

et al. 2002

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699

506

“…Peptide-induced and adoptive transfer EAE was induced as reported previously (19). Individual animals were observed daily and clinical scores were assessed in a blinded fashion on a 0 -5 scale as follows: 0 ϭ no abnormality; 1 ϭ limp tail or hind limb weakness; 2 ϭ limp tail and hind limb weakness; 3 ϭ hind limb paralysis; 4 ϭ hind limp paralysis and forelimb weakness; and 5 ϭ moribund.…”

Section: Induction and Clinical Evaluation Of Peptide-induced And Adomentioning

confidence: 99%

“…In vitro proliferation, delayed-type hypersensitivity (DTH), and ELISPOT assays DTH and ELISPOT assays were performed as reported previously (19). For proliferation assays, draining lymph nodes (LNs) (axillary, brachial, and inguinal) were harvested from naive mice or primed mice at indicated days following disease induction, counted, and cultured in 96-well microtiter plates at a density of 5 ϫ 10 5 cells/well in a total volume of 200 l of HL-1 medium (BioWhittaker; 1% penicillin/streptavidin and 1% glutamine).…”

Section: Coupled-cell Tolerancementioning

confidence: 99%

Peripheral Tolerance Induction Using Ethylenecarbodiimide-Fixed APCs Uses both Direct and Indirect Mechanisms of Antigen Presentation for Prevention of Experimental Autoimmune Encephalomyelitis

Turley

Miller

2007

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116

142

MHC class II (MHC II)-restricted T cell responses are a common driving force of autoimmune disease. Accordingly, numerous therapeutic strategies target CD4+ T cells with the hope of attenuating autoimmune responses and restoring self-tolerance. We have previously reported that i.v. treatment with Ag-pulsed, ethylenecarbodiimide (ECDI)-fixed splenocytes (Ag-SPs) is an efficient protocol to induce Ag-specific tolerance for prevention and treatment of experimental autoimmune encephalomyelitis (EAE). Ag-SPs coupled with peptide can directly present peptide:MHC II complexes to target CD4+ T cells in the absence of costimulation to induce anergy. However, Ag-SPs coupled with whole protein also efficiently attenuates Ag-specific T cell responses suggesting the potential contribution of alternative indirect mechanisms/interactions between the Ag-SPs and target CD4+ T cells. Thus, we investigated whether MHC II compatibility was essential to the underlying mechanisms by which Ag-SP induces tolerance during autoimmune disease. Using MHC-deficient, allogeneic, and/or syngeneic donor Ag-SPs, we show that MHC compatibility between the Ag-SP donor and the host is not required for tolerance induction. Interestingly, we found that ECDI treatment induces apoptosis of the donor cell population which promotes uptake and reprocessing of donor cell peptides by host APCs resulting in the apparent MHC II-independent induction of tolerance. However, syngeneic donor cells are more efficient at inducing tolerance, suggesting that Ag-SPs induce functional Ag-SP tolerance via both direct and indirect (cross-tolerance) mechanisms leading to prevention and effective treatment of autoimmune disease.

“…The MOG 35-55 (MEVGWYRSPFSRVVHLYRNGK), PLP 178 -191 (N TWTTCQSIAFPSK) (27), and MBP 54 -72 (SHHAARTTHYGSLPQKS QR) (28) are ID peptides in C57BL/6 mice. The MOG 113-127 (LKVE DPFYWVSPGVL), MOG 120 -134 (YWVSPGVLTLIALVP), MOG 183-197 (FVIVPVLGPLVALII) have been described as potential SD peptides of MOG (6).…”

Section: Peptide and Proteinmentioning

confidence: 99%

T Cell Repertoire Diversity Is Required for Relapses in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

Fazilleau

Delarasse

Motta

et al. 2007

Comparison of TCRαβ repertoires of myelin oligodendrocyte glycoprotein (MOG)-specific T lymphocytes in C57BL/6 and TdT-deficient littermates (TdT−/−) generated during experimental autoimmune encephalomyelitis (EAE) highlights a link between a diversified TCRαβ repertoire and EAE relapses. At the onset of the disease, the EAE-severity is identical in TdT+/− and TdT−/− mice and the neuropathologic public MOG-specific T cell repertoires express closely similar public Vα-Jα and Vβ-Jβ rearrangements in both strains. However, whereas TdT+/+ and TdT+/− mice undergo successive EAE relapses, TdT−/− mice recover definitively and the lack of relapses does not stem from dominant regulatory mechanisms. During the first relapse of the disease in TdT+/− mice, new public Vα-Jα and Vβ-Jβ rearrangements emerge that are distinct from those detected at the onset of the disease. Most of these rearrangements contain N additions and are found in CNS-infiltrating T lymphocytes. Furthermore, CD4+ T splenocytes bearing these rearrangements proliferate to the immunodominant epitope of MOG and not to other immunodominant epitopes of proteolipid protein and myelin basic protein autoantigens, excluding epitope spreading to these myelin proteins. Thus, in addition to epitope spreading, a novel mechanism involving TCRαβ repertoire diversification contributes to autoimmune progression.