Selective delivery of beta cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice.
Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet beta cells. Cytotoxic CD8(+) T cells, reactive to beta cell antigens, are required for T1D development in the NOD mouse model of the disease, and CD8(+) T cells specific for beta cell antigens can be detected in the peripheral blood of T1D patients. It has been evident that in nonautoimmune-prone mice, dendritic cells (DCs) present model antigens in a tolerogenic manner in the steady state, e.g., in the absence of infection, and cause T cells to proliferate initially but then to be deleted or rendered unresponsive. However, this fundamental concept has not been evaluated in the setting of a spontaneous autoimmune disease. To do so, we delivered a mimotope peptide, recognized by the diabetogenic CD8(+) T cell clone AI4, to DCs in NOD mice via the endocytic receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was followed by deletion. Tolerance was achieved because rechallenge of mice with the mimotope peptide in adjuvant did not induce an immune response. Thus, targeting of DCs with beta cell antigens leads to deletion of autoreactive CD8(+) T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. Our results provide support for the development of DC targeting of self antigens for treatment of chronic T cell-mediated autoimmune diseases.
Mukhopadhaya
Arunika
A
Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Hanafusa
Tadashi
T
Jarchum
Irene
I
Chen
Yi-Guang
YG
Iwai
Yoshiko
Y
Serreze
David V
DV
Steinman
Ralph M
RM
Tarbell
Kristin V
KV
DiLorenzo
Teresa P
TP
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D016688:Mice, Inbred NOD; D015778:Minor Histocompatibility Antigens; D010455:Peptides / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology
D000906:Antibodies; D015703:Antigens, CD; D001324:Autoantigens; C093569:DEC-205 receptor; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D011956:Receptors, Cell Surface