Encephalitogenic T cell clones specific for myelin basic protein. An unusual bias in antigen recognition.

Zamvil, Scott S.; Nelson, Phillip G.; Mitchell, Dennis J.; Knobler, Robert L.; Fritz, Robert B.; Steinman, Lawrence

doi:10.1084/jem.162.6.2107

Cited by 140 publications

(85 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is similar to the B10.PL bias in the pattern of responsiveness to the self Ag MBP or the foreign Ag hen egg lysozyme in (SJL ϫ B10.PL)F 1 mice (43)(44)(45). In earlier cases, bias in responsiveness had been suggested to correlate with lower expression or affinity of I-A s molecules for the Ag.…”

Section: Discussionsupporting

confidence: 55%

Immunodominance in the TCR Repertoire of αTCR Peptide-Specific CD4+ Treg Population That Controls Experimental Autoimmune Encephalomyelitis

Madakamutil

Maricic

Sercarz

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

Immunodominance in self-Ag-reactive pathogenic CD4+ T cells has been well established in several experimental models. Although it is clear that regulatory lymphocytes (Treg) play a crucial role in the control of autoreactive cells, it is still not clear whether immunodominant CD4+ Treg clones are also involved in control of autoreactivity. We have shown that TCR-peptide-reactive CD4+ and CD8+ Treg play an important role in the spontaneous recovery and resistance from reinduction of experimental autoimmune encephalomyelitis in B10.PL mice. We report, by sequencing of the TCR α- and β-chain associated with CD4+ Treg, that the TCR repertoire is limited and the majority of CD4+ Treg use the TCR Vβ14 and Vα4 gene segments. Interestingly, sequencing and spectratyping data of cloned and polyclonal Treg populations revealed that a dominant public CD4+ Treg clonotype expressing Vβ14-Jβ1.2 with a CDR3 length of 7 aa exists in the naive peripheral repertoire and is expanded during the course of recovery from experimental autoimmune encephalomyelitis. Furthermore, a higher frequency of CD4+ Treg clones in the naive repertoire correlates with less severity and more rapid spontaneous recovery from disease in parental B10.PL or PL/J and (B10.PL × PL/J)F1 mice. These findings suggest that unlike the Ag-nonspecific, diverse TCR repertoire among the CD25+CD4+ Treg population, TCR-peptide-reactive CD4+ Treg involved in negative feedback regulation of autoimmunity use a highly limited TCR V-gene repertoire. Thus, a selective set of immunodominant Treg as well as pathogenic T cell clones can be targeted for potential intervention in autoimmune disease conditions.

show abstract

Section: Discussionsupporting

confidence: 55%

Immunodominance in the TCR Repertoire of αTCR Peptide-Specific CD4+ Treg Population That Controls Experimental Autoimmune Encephalomyelitis

Madakamutil

Maricic

Sercarz

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…However, complex polymorphisms which could result in unbalanced MHC expression (29) need to be taken into consideration to devise effective Ag-specific therapy against the disease.…”

Section: Discussionmentioning

confidence: 99%

In Trans T Cell Tolerance Diminishes Autoantibody Responses and Exacerbates Experimental Allergic Encephalomyelitis

Bell

Divekar

Ellis

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

A number of Ag-specific approaches have been developed that ameliorate experimental allergic encephalomyelitis (EAE), an animal model for the human autoimmune disease multiple sclerosis. Translation to humans, however, remains a consideration, justifying the search for more insight into the mechanism underlying restoration of self-tolerance. Ig-proteolipid protein (PLP) 1 and Ig-myelin oligodendrocyte glycoprotein (MOG) are Ig chimeras carrying the encephalitogenic PLP 139–151 and MOG 35–55 amino acid sequence, respectively. Ig-PLP1 ameliorates EAE in SJL/J (H-2s) mice while Ig-MOG modulates the disease in C57BL/6 (H-2b) animals. In this study, we asked whether the chimeras would suppress EAE in F1 mice expressing both parental MHC alleles and representing a polymorphism with more relevance to human circumstances. The results show that Ig-MOG modulates both PLP1 and MOG peptide-induced EAE in the F1 mice, whereas Ig-PLP1 counters PLP1 EAE but exacerbates MOG-induced disease. This in trans aggravation of MOG EAE by Ig-PLP1 operates through induction of PLP1-specific T cells producing IL-5 that sustained inhibition of MOG-specific Abs leading to exacerbation of EAE. Thus, in trans T cell tolerance, which should be operative in polymorphic systems, can aggravate rather than ameliorate autoimmunity. This phenomenon possibly takes place through interference with protective humoral immunity.

show abstract

“…This peptide has been shown to be encephalitogenic in k and u haplotype mice, causing experimental allergic encephalomyelitis (EAE), a disease very similar to multiple sclerosis (37,38). The susceptibility of mice to this disease is governed by genes in the I region (39,40), and I-A restricted MBP1-37-specific T-cell clones have recently been described that also produce disease when administered in vivo (41,42). Residues 12-14 in the k and u chains are markedly different from those of the other five chains.…”

Section: Methodsmentioning

confidence: 99%

Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones.

Estess¹,

Begovich²,

Koo³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

100

View full text Add to dashboard Cite

domain variability is clustered into three discrete regions, two of which divide the Ap chains into subgroups, suggesting an evolutionary history for the separation of alleles in inbred strains of mice. The amino acid sequences of these five chains are compared to each other and to previously published I-Ap chains. Correlations are made between the primary structural differences and the serologic and immune response characteristics mapping to the I-A subregion.The intimate relationship between I-region associated (Ia) antigens and immune responsiveness to a multitude of natural and synthetic antigens has been known for some time (1, 2).Recent studies using either anti-Ia antisera or monoclonal antibodies to block immune responses strongly suggest that Ia antigens are the products of immune response (Ir) genes (3-5), but how a limited number of Ia molecules differentially regulate responses to a myriad of antigens is yet to be resolved. It seems likely that their role in the presentation of antigen to imtnunocompetent cells is of fundamental importance and that primary structural alterations in the a and (3 chains of the class II heterodimer result in a failure to present antigen in a configuration appropriate for recognition. These alterations must also account for the multiple epitopes recognized by both anti-Ia antibodies and alloreactive T cells.In an effort to address the nature of primary structural differences among class II molecules and how these differences affect immune responses, we have undertaken the cloning and sequencing of cDNAs encoding I-Ap chains from several mouse haplotypes. This should facilitate the eventual assignment of particular serologic epitopes and restriction elements to specific amino acids in these chains. Such analysis is a first step in designing experiments in which immune responsiveness can be manipulated via structural alterations in Ia molecules and then, perhaps, understood. Clones hybridizing to the human DQp or the murine Al cDNA probes were tested for the presence of restriction enzyme sites consistent with AP but not Ed coding sequences (9). The longest such clones were subcloned into the EcoRI site ofpBR322 and from there into the EcoRI site of M13 mp8 for sequencing. Sequencing was performed by the dideoxysequencing method of Biggin et al. (10). All clones were sequenced using the M13 universal primer (UP) from the EcoRI ends, as shown in Fig. 1. In addition, five 18-bp synthetic oligonucleotide primers homologous to conserved regions of the known AP and DQO sequences (8,(11)(12)(13)(14) were constructed and used to obtain sequence information on portions of the clones inaccessible from the EcoRI ends (Fig. 1, B-H productive (8, 9, 11-17). MATERIALS AND METHODS

show abstract

Encephalitogenic T cell clones specific for myelin basic protein. An unusual bias in antigen recognition.

Cited by 140 publications

References 37 publications

Immunodominance in the TCR Repertoire of αTCR Peptide-Specific CD4+ Treg Population That Controls Experimental Autoimmune Encephalomyelitis

Immunodominance in the TCR Repertoire of αTCR Peptide-Specific CD4+ Treg Population That Controls Experimental Autoimmune Encephalomyelitis

In Trans T Cell Tolerance Diminishes Autoantibody Responses and Exacerbates Experimental Allergic Encephalomyelitis

Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones.

Contact Info

Product

Resources

About