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Monocytes from Patients with Type 1 Diabetes Spontaneously Secrete Proinflammatory Cytokines Inducing Th17 Cells¹

Elizabeth M. Bradshaw^*, Khadir Raddassi^*, Wassim Elyaman^*, Tihamer Orban, Peter A. Gottlieb, Sally C. Kent^2,* and David A. Hafler^2,3,*

^* Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 and Section of Immunology and Immunogenetics, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; and Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045

Autoimmune diseases including type 1 diabetes (T1D) are thought to have a Th1/Th17 bias. The underlying mechanisms driving the activation and differentiation of these proinflammatory T cells are unknown. We examined the monocytes isolated directly from the blood of T1D patients and found they spontaneously secreted the proinflammatory cytokines IL-1β and IL-6, which are known to induce and expand Th17 cells. Moreover, these in vivo-activated monocytes from T1D subjects induced more IL-17-secreting cells from memory T cells compared with monocytes from healthy control subjects. The induction of IL-17-secreting T cells by monocytes from T1D subjects was reduced in vitro with a combination of an IL-6-blocking Ab and IL-1R antagonist. In this study, we report a significant although modest increase in the frequency of IL-17-secreting cells in lymphocytes from long-term patients with T1D compared with healthy controls. These data suggest that the innate immune system in T1D may drive the adaptive immune system by expanding the Th17 population of effector T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These studies were supported by grants from the U.S. National Institutes of Health to D.A.H. (P01 AI045757, U19 AI046130, U19 AI070352, and P01 AI039671), E.M.B. (F32 AI651003), and W.E. (F32 NS059205). S.C.K. is supported by grants from the Juvenile Diabetes Research Foundation International. D.A.H. is also supported by a Jacob Javits Merit Award (NS2427) from the National Institute of Neurological Disorders and Stroke.

² S.C.K. and D.A.H. contributed equally to the work.

³ Address correspondence and reprint requests to Dr. David A. Hafler, NRB 641, 77 Avenue Louis Pasteur, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115. E-mail address: hafler{at}broad.mit.edu

⁴ Abbreviations used in this paper: NOD, nonobese diabetic; T1D, type 1 diabetes; T2D, type 2 diabetes; IL-1Ra, IL-1R antagonist.

⁵ The online version of this article contains supplemental material.