Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes.
Therapeutic regulatory T cells (Tregs) can reverse pre-established autoimmune pathology. In this study, using a mouse model of autoimmune diabetes, we aimed to determine the means by which therapeutic Tregs control islet inflammation. Islet Ag-specific Tregs infiltrated inflamed islets soon after infusion into prediabetic mice, which was quickly followed by a selective reduction of mRNA associated with effector T cells in the islets. This change was partially due to decreased CD8(+) T cell accumulation in the tissue. CD8(+) T cells that remained in the islets after Treg treatment were able to engage dendritic cells in a manner similar to that found in untreated mice, consistent with the retention of an activated phenotype by islet dendritic cells shortly after Treg treatment. Nonetheless, Treg treatment abrogated IFN-γ production by intraislet CD8(+) and CD4(+) T cells at the protein level with minimal effect on IFN-γ mRNA. Sustained expression of IFN-γ protein by effector T cells was dependent on common γ-chain cytokine activation of the mTOR pathway, which was suppressed in islet CD8(+) T cells in vivo after Treg treatment. These multifaceted mechanisms underlie the efficacy of therapeutic Treg subversion of effector T cell functions at the site of inflammation to restore normal tissue homeostasis.
Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
Ashley E
AE
Mahne
Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
Joanna E
JE
Klementowicz
Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
Annie
A
Chou
Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.
Vinh
V
Nguyen
Department of Surgery, University of California, San Francisco, San Francisco, CA 94143 Qizhi.Tang@ucsf.edu.
Qizhi
Q
Tang
D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology*; D008212:Lymphocyte Depletion; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D007371:Interferon-gamma; D058570:TOR Serine-Threonine Kinases