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J Immunol. 2017 Dec 1;199(11):3748-3756. doi: 10.4049/jimmunol.1700667. Epub 2017 Oct 23.

Thymic-Specific Serine Protease Limits Central Tolerance and Exacerbates Experimental Autoimmune Encephalomyelitis.

Serre L1,2,3, Girard M1,2,3, Ramadan A1,2,3, Menut P1,2,3, Rouquié N1,2,3, Lucca LE1,2,3, Mahiddine K1,2,3, Leobon B4, Mars LT1,2,3,5,6, Guerder S7,2,3.

Author information

1
INSERM, U1043, Toulouse F-31300, France.
2
CNRS, UMR5282, Toulouse F-31300, France.
3
Centre de Physiopathologie de Toulouse Purpan, Université Toulouse III Paul-Sabatier, Toulouse F-31300, France.
4
Department of Pediatric Cardiology and Cardiovascular Surgery, Children's Hospital of Toulouse, Toulouse F-31300, France.
5
INSERM UMR995, Lille Inflammation Research International Center, F-59000 Lille, France; and.
6
Centre d'Excellence LICEND and FHU IMMINeNT, Université Lille, F-59000 Lille, France.
7
INSERM, U1043, Toulouse F-31300, France; Sylvie.guerder@inserm.fr.

Abstract

The genetic predisposition to multiple sclerosis (MS) is most strongly conveyed by MHC class II haplotypes, possibly by shaping the autoimmune CD4 T cell repertoire. Whether Ag-processing enzymes contribute to MS susceptibility by editing the peptide repertoire presented by these MHC haplotypes is unclear. Thymus-specific serine protease (TSSP) is expressed by thymic epithelial cells and thymic dendritic cells (DCs) and, in these two stromal compartments, TSSP edits the peptide repertoire presented by class II molecules. We show in this article that TSSP increases experimental autoimmune encephalomyelitis severity by limiting central tolerance to myelin oligodendrocyte glycoprotein. The effect on experimental autoimmune encephalomyelitis severity was MHC class II allele dependent, because the lack of TSSP expression conferred protection in NOD mice but not in C57BL/6 mice. Importantly, although human thymic DCs express TSSP, individuals segregate into two groups having a high or 10-fold lower level of expression. Therefore, the level of TSSP expression by thymic DCs may modify the risk factors for MS conferred by some MHC class II haplotypes.

PMID:
29061767
DOI:
10.4049/jimmunol.1700667
[Indexed for MEDLINE]
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