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An altered CD8+ T cell epitope of insulin prevents type 1 diabetes in humanized NOD mice.


ABSTRACT: Autoreactive CD8+ T cells, which play an indispensable role in ? cell destruction, represent an emerging target for the prevention of type 1 diabetes (T1D). Altered peptide ligands (APLs) can efficiently induce antigen-specific T cells anergy, apoptosis or shifts in the immune response. Here, we found that HLA-A*0201-restricted CD8+ T cell responses against a primary ?-cell autoantigen insulin epitope InsB15-14 were present in both NOD.?2mnull.HHD NOD mice and T1D patients. We generated several APL candidates for InsB15-14 by residue substitution at the p6 position. Only H6F exhibited an inhibitory effect on mInsB15-14-specific CD8+ T cell responses in vitro. H6F treatment significantly reduced the T1D incidence, which was accompanied by diminished autoreactive CD8+ T cell responses to mInsB15-14, inhibited infiltration of CD8+ and CD4+ T cells in the pancreas and reduced pro-inflammatory cytokine production in pancreatic and splenic T cells in NOD.?2mnull.HHD mice. Mechanistically, H6F treatment significantly augmented a tiny portion of CD8+CD25+Foxp3+ T cells in the spleen and especially in the pancreas. This subset exhibited typical Treg phenotypes and required peptide-specific restimulation to exert immunosuppressive activity. Therefore, this APL H6F may be a promising candidate with potential clinical application value for antigen-specific prevention of T1D.

SUBMITTER: Zhang M 

PROVIDER: S-EPMC6804845 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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An altered CD8<sup>+</sup> T cell epitope of insulin prevents type 1 diabetes in humanized NOD mice.

Zhang Mengjun M   Wang Shufeng S   Guo Binbin B   Meng Gang G   Shu Chi C   Mai Wenli W   Zheng Qian Q   Chen Xiaoling X   Wu Yuzhang Y   Wang Li L  

Cellular & molecular immunology 20180628 6


Autoreactive CD8<sup>+</sup> T cells, which play an indispensable role in β cell destruction, represent an emerging target for the prevention of type 1 diabetes (T1D). Altered peptide ligands (APLs) can efficiently induce antigen-specific T cells anergy, apoptosis or shifts in the immune response. Here, we found that HLA-A*0201-restricted CD8<sup>+</sup> T cell responses against a primary β-cell autoantigen insulin epitope InsB1<sub>5-14</sub> were present in both NOD.β2m<sup>null</sup>.HHD NOD  ...[more]

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