Immunotargeting of insulin reactive CD8 T cells to prevent diabetes.
Insulin is one of the earliest targeted autoantigens in the immune destruction of insulin-producing beta cells by autoreactive CD4 and CD8 T cells in type 1 diabetes. In this study, we used Non-obese diabetic (NOD) transgenic T cells engineered to express MHC class I-insulin peptide complexes linked to a T cell activation component (InsCD3-ζ), to target insulin-reactive CD8 T cells. We showed that activated, but not naïve, InsCD3-ζ CD8 T cells killed diabetogenic insulin-reactive CD8 target cells in vitro, inducing antigen-specific cell death mediated via both the release of perforin and the Fas-Fas ligand pathway. In vivo, InsCD3-ζ CD8 T cells migrated to the pancreatic lymph nodes of NOD mice after adoptive transfer. Concomitant with this, infiltration of CD8 T cells was also reduced in the pancreatic islets. Finally, in vivo, we showed that diabetes induced by adoptive transfer of insulin-reactive T cells was reduced following injection of activated InsCD3-ζ CD8 T cells. Furthermore, young NOD mice injected with InsCD3-ζ CD8 T cells developed a lower incidence and delayed onset of diabetes. Thus, using this novel system we have demonstrated that InsCD3-ζ CD8 T cells can directly kill insulin-reactive CD8 T cells in vitro and by targeting insulin-specific CD8 T cells early in the course of disease alter the progression of spontaneous diabetes in vivo in NOD mice.
Scott
Gwen S
GS
Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Fishman
Sigal
S
Khai Siew
L
L
Margalit
Alon
A
Chapman
Stephen
S
Chervonsky
Alexander V
AV
Wen
Li
L
Gross
Gideon
G
Wong
F Susan
FS
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics
D001324:Autoantigens; D017252:CD3 Complex; D015395:Histocompatibility Antigens Class I; D007328:Insulin; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins