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Eur J Immunol. 2015 Jul;45(7):1946-56. doi: 10.1002/eji.201445290. Epub 2015 May 12.

Central tolerance spares the private high-avidity CD4(+) T-cell repertoire specific for an islet antigen in NOD mice.

Serre L1,2,3,4, Fazilleau N1,2,3,4, Guerder S1,2,3,4.

Author information

1
Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
2
INSERM, U1043, Toulouse, France.
3
CNRS, UMR5282, Toulouse, France.
4
Université Toulouse III Paul-Sabatier, Toulouse, France.

Abstract

Although central tolerance induces the deletion of most autoreactive T cells, some autoreactive T cells escape thymic censorship. Whether potentially harmful autoreactive T cells present distinct TCRαβ features remains unclear. Here, we analyzed the TCRαβ repertoire of CD4(+) T cells specific for the S100β protein, an islet antigen associated with type 1 diabetes. We found that diabetes-resistant NOD mice deficient for thymus specific serine protease (TSSP), a protease that impairs class II antigen presentation by thymic stromal cells, were hyporesponsive to the immunodominant S100β1-15 epitope, as compared to wild-type NOD mice, due to intrathymic negative selection. In both TSSP-deficient and wild-type NOD mice, the TCRαβ repertoire of S100β-specific CD4(+) T cells though diverse showed a specific bias for dominant TCRα rearrangements with limited CDR3α diversity. These dominant TCRα chains were public since they were found in all mice. They were of intermediate- to low-avidity. In contrast, high-avidity T cells expressed unique TCRs specific to each individual (private TCRs) and were only found in wild-type NOD mice. Hence, in NOD mice, the autoreactive CD4(+) T-cell compartment has two major components, a dominant and public low-avidity TCRα repertoire and a private high-avidity CD4(+) T-cell repertoire; the latter is deleted by re-enforced negative selection.

KEYWORDS:

Autoimmunity; Avidity; CD4+ T cells; NOD; T-cell tolerance; TCR repertoire

PMID:
25884569
DOI:
10.1002/eji.201445290
[Indexed for MEDLINE]
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