CD4+ CD25+ regulatory T-cells inhibit the islet innate immune response and promote islet engraftment.
Early islet cell loss is a significant problem in clinical islet cell transplantation. Diverse stress stimuli induce innate immune responses in islets that contribute to beta-cell dysfunction, inflammation, and loss. Here, we show that cytokine-stimulated murine islets express multiple inflammatory chemokines that recruit T-cells and thereby impair islet function in vitro and in vivo. Both nonislet ductal and exocrine elements and the individual islet cellular components contribute to this innate immune response. CD4+ CD25+ regulatory T-cells inhibit islet chemokine expression through a cell contact-dependent, soluble factor-independent mechanism and inhibit effector T-cell migration to the islet. Regulatory T-cells can also migrate to stimulated islets. Cotransfer of regulatory T-cells with islets in a transplantation model prevents islet innate immune responses and inflammation and preserves normal architecture and engraftment. Regulatory T-cell inhibition of multiple components of innate immune responses may be a fundamental aspect of their function that influences ischemia-reperfusion injury and adaptive immunity.
Chen
Dongmei
D
Department of Gene and Cell Medicine, and Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
Zhang
Nan
N
Fu
Shuang
S
Schröppel
Bernd
B
Guo
Qiongfen
Q
Garin
Alexandre
A
Lira
Sergio A
SA
Bromberg
Jonathan S
JS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis* / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology; D007113:Immunity, Innate; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013154:Spleen / Q000276:immunology
D018925:Chemokines; D016207:Cytokines; D015375:Receptors, Interleukin-2