Differential Tolerance Is Induced in T Cells Recognizing Distinct Epitopes of Myelin Basic Protein

Harrington, C.; Paez, Angela; Hunkapiller, Tim; Mannikko, Valerie; Brabb, Thea; Ahearn, MaryEllen; Beeson, Craig C.; Goverman, Joan

doi:10.1016/s1074-7613(00)80562-2

Cited by 171 publications

(172 citation statements)

References 45 publications

Supporting

Mentioning

159

Contrasting

Order By: Relevance

“…Goverman and colleagues [33] previously demonstrated that T cells recognizing MBP residues 121-150 were subject to central tolerance in wild-type mice, but would dominate the T cell repertoire in MBP -/-shiverer mice. This observation was striking because MBP 121-150 is not expressed by thymus components.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, we conceive that selftolerance to P0 is defective in the P0-deficient mice and that the Th1 responses to P0 inversely correlate with the transcription levels of P0 mRNA. Thus, we postulate that endogenous P0 may inactivate or eliminate P0-reactive T cells, as endogenous myelin basic protein (MBP) does for potentially encephalitogenic T cells [32][33][34].…”

Section: Increased Reactivity Of T Cells To P0 180-199 In P0-deficienmentioning

confidence: 99%

See 1 more Smart Citation

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

et al. 2003

View full text Add to dashboard Cite

Mice with a heterozygous null mutation in myelin protein zero (P0 +/-) develop late-onset clinical paralysis associated with inflammatory pathology in the peripheral nerves. Although the development of this illness is known to require T cells and macrophages, little is understood regarding the immunological defect in the mice. Here we report that young P0 +/-mice, free from clinical manifestations, have a defect in central tolerance to P0, and are more prone to induction of experimental autoimmune neuritis (EAN) by sensitization against P0 180-199 peptide. Notably, we found that the P0 gene is transcribed in the thymus of wild-type and the P0 +/-mice in an amount proportional to the gene dosage. We then replaced the thymus of wild-type mice with that of the P0-deficient mice and vice versa. Immunization of these mice with P0 [180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199] revealed that a lower thymic P0 transcript would be associated with the higher recall T cell response to P0 [180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199] , thus accounting for the higher susceptibility of the P0 +/-mice to P0-induced EAN. These results imply that a heterozygous mutation in an autoantigen could cause defective central tolerance to the autoantigen. As such, autoimmune T cells may play some role in "genetic" diseases caused by a heterozygous gene defect.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Increased Reactivity Of T Cells To P0 180-199 In P0-deficienmentioning

confidence: 99%

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

et al. 2003

View full text Add to dashboard Cite

show abstract

“…The blood was diluted four times with sterile saline, and PBMCs were obtained by density-gradient centrifugation over a Ficoll gradient. Single cell suspensions from dLN and nondraining LN and the spleen were prepared as previously described (1). For flow cytometric studies of the cell populations obtained, we used directly labeled Abs specified, all from PharMingen (San Diego, CA).…”

Section: Cell Preparation From the Various Organs Tested; Flow Cytometrymentioning

confidence: 99%

“…This is also the case for lymphocytes specific for the neuroantigen myelin basic protein (MBP) and proteolipid protein (PLP) (1)(2)(3). Low affinity cells, however, and T cells specific for determinants not expressed in the thymus escape this negative selection process.…”

mentioning

confidence: 99%

Frequencies of Neuroantigen-Specific T Cells in the Central Nervous System Versus the Immune Periphery During the Course of Experimental Allergic Encephalomyelitis

Targoni

Baus

Hofstetter

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

Direct measurements of the frequency and the cytokine signature of the neuroantigen-specific effector cells in experimental allergic encephalomyelitis (EAE) are a continuing challenge. This is true for lymphoid tissues, and more importantly, for the CNS itself. Using enzyme-linked immunospot analysis (ELISPOT) assays, we followed proteolipid protein (PLP) 139–151-specific T cells engaged by active immunization of SJL mice. The total numbers of PLP139–151-specific CD4 cells were highest before disease onset. At this time, these cells resided in lymphoid and nonlymphoid tissues, but were not detected in the CNS. While the PLP139–151-specific cells reached high frequencies in the CNS during clinical EAE, in absolute numbers, less than 20% of them were present in the target organ, with the majority residing in the periphery throughout all stages of the disease. The numbers of PLP139–151-specific cells gradually declined in both compartments with time. While eventually this first wave of effector cells completely disappeared from the CNS, PLP178–191-specific cells became engaged, being detected first in the CNS. These data suggest that throughout all stages of EAE, the effector cells in the CNS are recruited from a vast peripheral reservoir, and that the second wave of effector cells is engaged while the first wave undergoes exhaustion.

show abstract

“…Previous studies indicated that immune responses could be made to the self epitope that were absent in vivo as a result of a mutation in a self protein (13,14). Gapin et al demonstrated that ablation of the presentation in a single epitope of HEL in I-E dexpressing mice resulted in a complete lack of tolerance to it (13).…”

Section: Resultsmentioning

confidence: 99%

Cutting Edge: A Single MHC Anchor Residue Alters the Conformation of a Peptide-MHC Complex Inducing T Cells That Survive Negative Selection

Peterson

DiPaolo

Kanagawa

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

We generated transgenic mice that expressed hen egg-white lysozyme (HEL) under a class II MHC promoter. The A7 line expressed HEL with a point mutation in the Asp52 residue, the main anchor amino acid responsible for the selection of the chemically dominant family of peptides (52–60) by I-Ak molecules. Mice expressing HEL with Ala52 were completely unresponsive when immunized with the same protein, i.e., HEL A52. However, the same mice immunized with wild-type HEL elicited T cells that recognized a conformation of the 52–61 core sequence uniquely different between Asp52 and Ala52 containing peptides. Importantly, some T cells also recognized the HEL A52 peptide given exogenously but not the same peptide processed from HEL A52 protein. Thus, a core MHC anchor residue influences markedly the specificity of the T cells. We discuss the relevance of these findings to autoimmunity and vaccination with altered peptides.

show abstract

Differential Tolerance Is Induced in T Cells Recognizing Distinct Epitopes of Myelin Basic Protein

Cited by 171 publications

References 45 publications

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

Frequencies of Neuroantigen-Specific T Cells in the Central Nervous System Versus the Immune Periphery During the Course of Experimental Allergic Encephalomyelitis

Cutting Edge: A Single MHC Anchor Residue Alters the Conformation of a Peptide-MHC Complex Inducing T Cells That Survive Negative Selection

Contact Info

Product

Resources

About