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A key role for ICAM-1 in generating effector cells mediating inflammatory responses

Abstract

We investigated how the accessory molecule interactions encountered during T cell priming influence T cell–mediated destruction of insulin-producing β cells and lead to type 1 diabetes. T cell receptor (TCR)-transgenic CD4+ T cells were primed under controlled conditions in vitro before being adoptively transferred into transgenic recipients expressing membrane ovalbumin under the control of the rat insulin promoter (RIP-mOVA). During priming, antigen-presenting cell expression of B7-1 without intracellular adhesion molecule 1 (ICAM-1) led to the generation of effector cells that migrated to the pancreata of RIP-mOVA recipients but did not cause diabetes. In contrast, when T cells were primed with APCs expressing both B7-1 and ICAM-1, pronounced destruction of β cells and a rapid onset of diabetes were observed. Pathogenicity was associated with T cell production of the macrophage-attracting chemokines CCL3 and CCL4. Thus, interactions of lymphocyte function–associated antigen 1 with ICAM-1 during priming induce both qualitative and quantitative alterations in T effector function and induce potentially autodestructive responses.

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Figure 1: SC2.Ad.B7-1 and SC2.Ad.B7-1.ICAM-1 cells elicit strong proliferative responses that are equivalent in magnitude to T-depleted spleen cells.
Figure 2: SC2.Ad.B7-1.ICAM-1–primed D011 CD4+ cells induced insulitis and destruction of insulin-producing β cells.
Figure 3: Delayed onset of diabetes after adoptive transfer of CD4+ cells primed with ICAM-1–deficient APCs.
Figure 4: Immunohistochemical analysis of pancreas sections after adoptive transfer of SC2.Ad.B7-1– and SC2.Ad.B7-1.ICAM-1–primed cells.
Figure 5: In vitro responses of OVA peptide–specific CD4+ T cells taken from pancreatic draining lymph nodes.
Figure 6: Histochemical analysis of cytokines in the pancreas.
Figure 7: LFA-1–ICAM-1 up-regulate CCL3 and CCL4 chemokine mRNA expression.

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Acknowledgements

We thank B. Marchand for typing the manuscript and D. Redondo for technical assistance. Supported by grants CA41993, CA25803 and AI39664 from the United States Public Health Service, a grant from the Juvenile Diabetes Foundation and a grant from R. W. Johnson Pharmaceutical Research Institute.

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Correspondence to Susan R. Webb.

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Camacho, S., Heath, W., Carbone, F. et al. A key role for ICAM-1 in generating effector cells mediating inflammatory responses. Nat Immunol 2, 523–529 (2001). https://doi.org/10.1038/88720

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