Autoreactive CD8^(+)T cells,which play an indispensable role inβcell destruction,represent an emerging target for the prevention of type 1 diabetes(T1D).Altered peptide ligands(APLs)can efficiently induce antigen-spe...Autoreactive CD8^(+)T cells,which play an indispensable role inβcell 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 primaryβ-cell autoantigen insulin epitope InsB15–14 were present in both NOD.β2m null.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 mInsB1_(5–14)-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.β2m^(null).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.展开更多
基金supported by the National Natural Science Foundation of China(No.31570931 and No.31771002)the National Key Project for Research&Development of China(Grant no.2016YFA0502204).
文摘Autoreactive CD8^(+)T cells,which play an indispensable role inβcell 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 primaryβ-cell autoantigen insulin epitope InsB15–14 were present in both NOD.β2m null.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 mInsB1_(5–14)-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.β2m^(null).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.
