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

Abstract

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.

Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?

“…Douglas et al (2009) found that the majority of clinically healthy, unaffected monozygotic twins in discordant pairs failed to exhibit an IGF-IR ϩ skewed population of circulating T and B cells compared with their twin with Graves' disease. The study replicated observations made earlier by the same authors in a separate North American cohort of patients with sporadic Graves' disease (Douglas et al, 2007. It is noteworthy that this recent study demonstrates that the more frequent display of IGF-IR on T and B cells, associated with Graves' disease, seems to derive from acquired rather than genetic factors.…”

“…Unlike TAOderived orbital fibroblasts, in which cell-surface IGF-IR densities are 3-to 4-fold higher than those on control cells, receptor levels on T cells from patients with Graves' disease are similar to those found on control lymphocytes (Douglas et al, 2007). As with fibroblasts, T cells bearing the IGF-IR ϩ phenotype exhibit preferential resistance to apoptosis and a growth advantage in vitro.…”

“…Examination of circulating T cells from patients with Graves' disease has disclosed an over-abundance of IGF-IR ϩ lymphocytes (Fig. 6) (Douglas et al, 2007). The frequency of receptor-harboring T cells was found to be increased from controls, in which 15 Ϯ 3% of CD3 ϩ T cells expressed the receptor compared with 48 Ϯ 5% (n ϭ 33, p Յ 10 Ϫ8 versus control) among those from patients.…”

Human fibrocytes coexpress thyroglobulin and thyrotropin receptor

“…They were washed, resuspended in staining buffer at 4°C, and subjected to FACS analysis in a Calibur flow cytometer (BD). For intracellular Tg staining, cells were permeabilized as reported (39). Mean fluorescent intensity is the ratio of mean fluorescence sample:isotype control fluorescence.…”

Divergent Frequencies of IGF-I Receptor-Expressing Blood Lymphocytes in Monozygotic Twin Pairs Discordant for Graves’ Disease: Evidence for a Phenotypic Signature Ascribable to Nongenetic Factors

“…Overrepresentation of IGF-IR-expressing lymphocytes has recently been described. T cells isolated from orbital connective tissue and those circulating in peripheral blood of patients with GD demonstrate increased IGF-IR display (7). The IGF-IR ϩ phenotype is found in a disproportionate fraction of CD45RO ϩ (memory) CD4 ϩ , and memory CD8 ϩ T cells.…”