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β cells are responsible for CXCR3-mediated T-cell infiltration in insulitis

Abstract

T cell–mediated loss of insulin-secreting β cells in the islets of Langerhans is the hallmark of type 1 diabetes. The molecular basis for the directed migration of autoreactive T cells leading to insulitis is presently unknown. Here we demonstrate that in response to inflammation, β cells secrete the chemokines CXC ligand 10 and CXC ligand 9, which specifically attract T-effector cells via the CXC chemokine receptor 3. In mice deficient for this receptor, the onset of type 1 diabetes is substantially delayed. Thus, in the absence of known etiological agents, CXC receptor 3 represents a novel target for therapeutic interference early in type 1 diabetes.

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Figure 1: RT-PCR analyses of chemokine mRNA expression in wild-type islets and NIT-1 cells, or cytokine, chemokine and chemokine-receptor mRNA expression in wild-type and RIP-GP transgenic islets following LCMV infection.
Figure 2: Immunohistochemistry of wild-type and RIP-GP islets after LCMV infection.
Figure 3: Peripheral T-cell migration and expression of chemokines, chemokine receptors, CD4/CD8 and IFN-γ in islets of LCMV-infected RIP-GP transgenic mice.
Figure 4: T-cell migration towards NIT-1 cell supernatants.
Figure 5: Delayed insulitis and onset of diabetes in CXCR3-deficient mice.

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Acknowledgements

We thank H. Hengartner, R.M. Zinkernagel, E. Palmer and W. Krenger for discussions, critical review of the manuscript and the provision of RIP-GP mice; S. Hugi, E. Christen, V. Wyss and B. Odermatt for technical help; M. Török for assistance with real-time quantitative PCR; and R. Geissmann and M. Gaio for secretarial assistance.

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Correspondence to Georg A. Holländer.

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Frigerio, S., Junt, T., Lu, B. et al. β cells are responsible for CXCR3-mediated T-cell infiltration in insulitis. Nat Med 8, 1414–1420 (2002). https://doi.org/10.1038/nm1202-792

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