Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis

The development of autoimmune disease is accompanied by the acquired recognition of new self-determinants, a process commonly referred to as determinant spreading. In this study, we addressed the question of whether determinant spreading is pathogenic for progression of chronic-relapsing experimental autoimmune encephalomyelitis (EAE), a disease with many similarities to multiple sclerosis (MS). Our approach involved a systematic epitope mapping of responses to myelin proteolipid protein (PLP) as well as assaying responses to known encephalitogenic determinants of myelin basic protein (MBP 87-89) and myelin oligodendrocyte glycoprotein (MOG 92-106) at various times after induction of EAE in (SWR X SJL)F1 mice immunized with PLP 139-151. We found that the order in which new determinants are recognized during the course of disease follows a predictable sequential pattern. At monthly intervals after immunization with p139-151, responses to PLP 249-273, MBP 87-99, and PLP 137-198 were sequentially accumulated in al mice examined. Three lines of evidence showed that determinant spreading is pathogenic for disease progression: (a) spreading determinants mediate passive transfer of acute EAE in naive (SWR X SJL)F1 recipients; (b) an invariant relationship exists between the development of relapse/progression and the spreading of recognition to new immunodominant encephalitogenic determinants; and (c) after EAE onset, the induction of peptide-specific tolerance to spreading but not to nonspreading encephalitogenic determinants prevents subsequent progression of EAE. Thus, the predictability of acquired self-determinant recognition provides a basis for sequential determinant-specific therapeutic intervention after onset of the autoimmune disease process.

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High Frequency of Autoreactive Myelin Proteolipid Protein–Specific T Cells in the Periphery of Naive Mice

Journal of Experimental Medicine ◽

10.1084/jem.191.5.761 ◽

2000 ◽

Vol 191 (5) ◽

pp. 761-770 ◽

Cited By ~ 207

Author(s):

Ana C. Anderson ◽

Lindsay B. Nicholson ◽

Kevin L. Legge ◽

Vadim Turchin ◽

Habib Zaghouani ◽

...

Keyword(s):

T Cells ◽

High Frequency ◽

Proteolipid Protein ◽

Autoimmune Encephalomyelitis ◽

Myelin Proteolipid Protein ◽

Central Tolerance ◽

Environmental Agents ◽

Similar Affinity ◽

Myelin Proteolipid ◽

Experimental Autoimmune

The autoreactive T cells that escape central tolerance and form the peripheral self-reactive repertoire determine both susceptibility to autoimmune disease and the epitope dominance of a specific autoantigen. SJL (H-2s) mice are highly susceptible to the induction of experimental autoimmune encephalomyelitis (EAE) with myelin proteolipid protein (PLP). The two major encephalitogenic epitopes of PLP (PLP 139–151 and PLP 178–191) bind to IAs with similar affinity; however, the immune response to the PLP 139–151 epitope is always dominant. The immunodominance of the PLP 139–151 epitope in SJL mice appears to be due to the presence of expanded numbers of T cells (frequency of 1/20,000 CD4+ cells) reactive to PLP 139–151 in the peripheral repertoire of naive mice. Neither the PLP autoantigen nor infectious environmental agents appear to be responsible for this expanded repertoire, as endogenous PLP 139–151 reactivity is found in both PLP-deficient and germ-free mice. The high frequency of PLP 139–151-reactive T cells in SJL mice is partly due to lack of thymic deletion to PLP 139–151, as the DM20 isoform of PLP (which lacks residues 116–150) is more abundantly expressed in the thymus than full-length PLP. Reexpression of PLP 139–151 in the embryonic thymus results in a significant reduction of PLP 139–151-reactive precursors in naive mice. Thus, escape from central tolerance, combined with peripheral expansion by cross-reactive antigen(s), appears to be responsible for the high frequency of PLP 139–151-reactive T cells.

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B Cell Regulation of CD4+CD25+T Regulatory Cells and IL-10 Via B7 is Essential for Recovery From Experimental Autoimmune Encephalomyelitis

The Journal of Immunology ◽

10.4049/jimmunol.178.6.3447 ◽

2007 ◽

Vol 178 (6) ◽

pp. 3447-3456 ◽

Cited By ~ 226

Author(s):

Monica K. Mann ◽

Katarzyna Maresz ◽

Leah P. Shriver ◽

Yanping Tan ◽

Bonnie N. Dittel

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

B Cell ◽

T Regulatory Cells ◽

Regulatory Cells ◽

Cell Regulation ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

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Priming of Myelin-Specific T Cells in the Absence of Dendritic Cells Results in Accelerated Development of Experimental Autoimmune Encephalomyelitis

10.1101/2020.12.28.424609 ◽

2020 ◽

Author(s):

Thaiphi Luu ◽

Julie F. Cheung ◽

Hanspeter Waldner

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Experimental Autoimmune Encephalomyelitis ◽

T Cell Responses ◽

Proteolipid Protein ◽

Cell Receptor ◽

Autoimmune Encephalomyelitis ◽

Cell Responses ◽

Experimental Autoimmune

AbstractExperimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is predominantly mediated by pro-inflammatory CD4+ T cell responses to CNS antigens, including myelin proteolipid protein (PLP). Dendritic cells (DCs) are considered critical for inducing T cell responses against infectious agents, but the importance of DCs in priming self-reactive CD4+ T cells in autoimmune disease such as MS has been unclear.To determine the requirement of DCs in PLP-specific CD4+ T cell responses and EAE, we genetically deleted CD11c+ DCs in PLP T cell receptor (TCR) transgenic SJL mice constitutively. DC deficiency did not impair the development, selection or the pathogenic function of PLP-specific CD4+ T cells in these mice, and resulted in accelerated spontaneous EAE compared to DC sufficient controls. In addition, using a genetic approach to ablate DCs conditionally in SJL mice, we show that CD11c+ DCs were dispensable for presenting exogenous or endogenous myelin antigen to PLP-specific T cells and for promoting pro-inflammatory T cell responses and severe EAE. Our findings demonstrate that constitutive or conditional ablation of CD11c+ DCs diminished self-tolerance to PLP autoantigen. They further show that in the absence of DCs, non-DCs can efficiently present CNS myelin antigens such as PLP to self-reactive T cells, resulting in accelerated onset of spontaneous or induced EAE.

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