Reversal of autoimmunity by boosting memory-like autoregulatory T cells.
Blunting autoreactivity without compromising immunity remains an elusive goal in the treatment of autoimmunity. We show that progression to autoimmune diabetes results in the conversion of naive low-avidity autoreactive CD8(+) T cells into memory-like autoregulatory cells that can be expanded in vivo with nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHC-NP). Treatment of NOD mice with monospecific pMHC-NPs expanded cognate autoregulatory T cells, suppressed the recruitment of noncognate specificities, prevented disease in prediabetic mice, and restored normoglycemia in diabetic animals. pMHC-NP therapy was inconsequential in mice engineered to bear an immune system unresponsive to the corresponding epitope, owing to absence of epitope-experienced autoregulatory T cells. pMHC-NP-expanded autoregulatory T cells suppressed local presentation of autoantigens in an interferon-gamma-, indoleamine 2,3-dioxygenase-, and perforin-dependent manner. Nanoparticles coated with human diabetes-relevant pHLA complexes restored normoglycemia in a humanized model of diabetes. These observations expose a paradigm in the pathogenesis of autoimmunity amenable for therapeutic intervention.
Tsai
Sue
S
Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases, The University of Calgary, 3330 Hospital Drive N.W., Calgary, AB T2N 4N1, Canada.
Shameli
Afshin
A
Yamanouchi
Jun
J
Clemente-Casares
Xavier
X
Wang
Jinguo
J
Serra
Pau
P
Yang
Yang
Y
Medarova
Zdravka
Z
Moore
Anna
A
Santamaria
Pere
P
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D015551:Autoimmunity; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D005260:Female; D005952:Glucose-6-Phosphatase / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D054353:Perforin / Q000276:immunology; D011506:Proteins / Q000737:chemistry / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011506:Proteins; D054353:Perforin; D007371:Interferon-gamma; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse