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Aberrant Expression of the Insulin-Like Growth Factor-1 Receptor by T Cells from Patients with Graves’ Disease May Carry Functional Consequences for Disease Pathogenesis¹

Raymond S. Douglas^*,,, Andrew G. Gianoukakis^*,, Shweta Kamat^* and Terry J. Smith^2,*,,

^* Department of Medicine, Division of Molecular Medicine, Harbor-University of California Los Angeles Medical Center, and Los Angeles Biomedical Research Institute, Torrance, CA 90502; Jules Stein Eye Institute, Los Angeles, CA 90095; and David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095

Graves’ disease (GD), an autoimmune process involving thyroid and orbital tissue, is associated with lymphocyte abnormalities including expansion of memory T cells. Insulin-like growth factor receptor-1 (IGF-1R)-bearing fibroblasts overpopulate connective tissues in GD. IGF-1R on fibroblasts, when ligated with IgGs from these patients, results in the expression of the T cell chemoattractants, IL-16 and RANTES. We now report that a disproportionately large fraction of peripheral blood T cells express IGF-1R (CD3⁺IGF-R⁺). CD3⁺IGF-1R⁺ T cells comprise 48 ± 4% (mean ± SE; n = 33) in patients with GD compared with 15 ± 3% (n = 21; p < 10^–8) in controls. This increased population of IGF-1R⁺ T cells results, at least in part, from an expansion of CD45RO⁺ T cells expressing the receptor. In contrast, the fraction of CD45RA⁺IGF-1R⁺ T cells is similar in GD and controls. T cells harvested from affected orbital tissues in GD reflect similar differences in the proportion of IGF-1R⁺CD3⁺ and IGF-1R⁺CD4⁺CD3⁺ cells as those found in the peripheral circulation. GD-derived peripheral T cells express durable, constitutive IGF-1R expression in culture and receptor levels are further up-regulated following CD3 complex activation. IGF-1 enhanced GD-derived T cell incorporation of BrdU (p < 0.02) and inhibited Fas-mediated apoptosis (p < 0.02). These findings suggest a potential role for IGF-1R displayed by lymphocytes in supporting the expansion of memory T cells in GD.

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 This work was funded in part by Grants EY016339 (to R.S.D.), RR017304 (to A.G.G.), EY008976, EY011708, and DK063121 (to T.J.S.), and RR00425 from the National Institutes of Health. We gratefully acknowledge generous support from Steve and Kathleen Flynn and the Bell Charitable Foundation.

² Address correspondence and reprint requests to Dr. Terry J. Smith, Division of Molecular Medicine, Harbor-University of California Los Angeles Medical Center, Building C-2, 1124 West Carson Street, Torrance, CA 90502. E-mail address: tjsmith{at}ucla.edu

³ Abbreviations used in this paper: IGF-1R, insulin-like growth factor receptor-1; GD, Graves’ disease; TAO, thyroid-associated ophthalmopathy; MFI, mean fluorescent intensity; 7-AAD, 7-aminoactinomycin D.

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