Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention

Acha‐Orbea, Hans; Mitchell, Dennis J.; Timmermann, Lars; Wraith, David C.; Tausch, Gilbert S.; Waldor, Matthew K.; Zamvil, Scott S.; McDevitt, Hugh O.; Steinman, Lawrence

doi:10.1016/0092-8674(88)90558-2

Cited by 912 publications

(391 citation statements)

References 68 publications

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“…DNA prepared from 25 clones was digested with Hind III, Eco RI, and Bam HI, and Southern blots were tested for TCR rearrangements, using a series of oz and (3 TCR probes . 5 of the 25 clones (11,19,14,23, and 28) turned out to be repeated isolates, since they were identical in terms of strain of origin, immunization number, and all primary and secondary TCR rearrangements with another clone (Tables II and III). However, the remaining 20 clones could be unequivocally judged as unique by the same criteria .…”

Section: Resultsmentioning

confidence: 99%

“…In fact, the A chain loop has been shown to remain intact even in the acidic late endosomes of rat liver cells (43) . This determinant, in contrast to many others presented usually in linear or u helical form (6,7,14,17), attracts a relatively large number of diff erent T cell clones . We assume that the privileged status of this determinant is related to the loop structure, since our preliminary studies suggest that immunization with oxidized (extended) A chain F may induce a T cell response of narrow clonal spectrum (F. Falcioni, unpublished results) .…”

Section: Discussionmentioning

confidence: 99%

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Flexibility of the T cell repertoire. Self tolerance causes a shift of T cell receptor gene usage in response to insulin.

Falcioni¹,

Dembić²,

Müller³

et al. 1990

The Journal of Experimental Medicine

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Bovine insulin(BI)-specific I-Ab-restricted T cell clones have been characterized for fine specificity and TCR gene usage. We have demonstrated that mouse strains carrying H-2b on three different genetic backgrounds (C57BL, BALB, and 129) rearrange and express the V beta 6 gene in a large proportion (36%) of insulin-specific clones. In these strains, the non-MHC background did not seem to influence TCR gene usage in response to BI. The V beta 6+ clones appeared to be selected by the antigen. In contrast, no V beta 6+ clones could be isolated from (B6 x DBA/2)F1 mice, where V beta 6+ (and V beta 8.1+) T cells are deleted by self tolerance to Mls-1a. Thus, although a small proportion of residual V beta 6+ cells had been demonstrated in Mls-1a mice, these cells could not be retrieved in a response that uses V beta 6 predominantly. In functional terms, therefore, the deletion of V beta 6 by self tolerance appears to be complete. Instead of V beta 6, the majority (up to 60%) of I-Ab- as well as I-Ad-restricted insulin-specific clones from the (B6 x DBA/2)F1 mice expressed V beta 8.2 and V beta 8.3. This shift of gene usage was not accompanied by any detectable change in the fine specificity pattern of response. Thus, in the insulin-specific response, the flexibility of T cell repertoire fully compensates for deletions caused by self tolerance.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Flexibility of the T cell repertoire. Self tolerance causes a shift of T cell receptor gene usage in response to insulin.

Falcioni¹,

Dembić²,

Müller³

et al. 1990

The Journal of Experimental Medicine

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“…The residual repertoire of unique TCRs following thymic selection is between 10 and 100 million in humans (1). Despite this vast potential repertoire, immune responses often show strong bias in TCR selection, resulting in immunodominance of certain "public" TCRs that are widely used in individuals with shared MHC types (2)(3)(4)(5). Structural studies have shown that biased TCR usage arises from unique specificity requirements for a given peptide-MHC complex (6,7).…”

mentioning

confidence: 99%

The Impact of a Large and Frequent Deletion in the Human TCR β Locus on Antiviral Immunity

Brennan

Petersen

Neller

et al. 2012

The Journal of Immunology

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The TCR plays a critical role in recognizing intracellular pathogens and initiating pathways leading to the destruction of infected cells by the immune system. Although genetic variability is known to greatly impact on the human immune system and the outcome of infection, the influence of sequence variation leading to the inactivation or deletion of TCR gene segments is unknown. To investigate this issue, we examined the CD8+ T cell response to an HLA-B7–restricted epitope (265RPHERNGFTVL275) from the pp65 Ag of human CMV that was highly biased and frequently dominated by a public TCR β-chain encoded by the variable gene segment TRBV4-3. Approximately 40% of humans lack T cells expressing TRBV4-3 because of a 21.5-kb insertion/deletion polymorphism, but these individuals remain responsive to this epitope, using a diverse T cell repertoire characterized by private TCR usage. Although most residues within the bulged 11-mer peptide were accessible for TCR contact, the public and private TCRs showed distinct patterns of sensitivity to amino acid substitution at different positions within the peptide, thereby suggesting that the repertoire diversity generated in the absence of the dominant public TRBV4-3+ TCR could lead to better protection from viral escape mutation. Thus, variation in the size of the TRBV repertoire clearly contributes toward interindividual variability in immune responses and is presumably maintained in many ethnic groups to enhance the diversity of Ag-specific T cell responses.

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“…The restricted TCR V gene usage and shifts in the T cell repertoire toward limited epitopes of autoantigens have been elegantly demonstrated in rodent experimental models (27,28). Evidence begins to emerge in some human autoimmune diseases where autoreactive T cells are found to undergo clonal activation and expansion.…”

Section: Discussionmentioning

confidence: 99%

Clonal expansion of mycobacterial heat‐shock protein–reactive T lymphocytes in the synovial fluid and blood of rheumatoid arthritis patients

Celis¹,

Vandevyver²,

Geusens³

et al. 1997

Arthritis & Rheumatism

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Objective. To examine the reactivity pattern and T cell receptor (TCR) characteristics of mycobacterial heat-shock protein 65 (hsp65)-reactive T cells generated from paired synovial fluid (SF) and peripheral blood (PB) samples obtained from rheumatoid arthritis (RA) patients and from healthy subjects.Methods. The reactivity pattern of hsp65-reactive T cell clones generated under limiting-dilution conditions was analyzed in 3H-thymidine incorporation assays. The TCR variable regions of these hsp65-reactive T cells were characterized by polymerase chain reaction with TCR AV-and BV-specific primers and by DNA sequence analysis of the third complementaritydetermining region (CDR3).Results. The hsp65-reactive T cells derived both from RA patients and controls preferentially recognized the 1-170 and 303-540 regions of hsp65 and did not cross-react with human hsp60. The hsp65-reactive T cell clones derived from RA patients displayed a restricted TCR AV and BV gene usage, which can be attributed to the limited clonal origin(s) of the independent T cell clones, as evidenced by CDR3 sequence analysis. These clonally expanded T cells were found in both PB and SF and in different inflamed joints of RA patients.Conclusion. Our study suggests that there is in vivo clonal activation and expansion of mycobacterial hsp65-reactive T cells in patients with RA.

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Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention

Cited by 912 publications

References 68 publications

Flexibility of the T cell repertoire. Self tolerance causes a shift of T cell receptor gene usage in response to insulin.

Flexibility of the T cell repertoire. Self tolerance causes a shift of T cell receptor gene usage in response to insulin.

The Impact of a Large and Frequent Deletion in the Human TCR β Locus on Antiviral Immunity

Clonal expansion of mycobacterial heat‐shock protein–reactive T lymphocytes in the synovial fluid and blood of rheumatoid arthritis patients

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