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B. P. Vistica, A. B. D. Collins, H. Yin, C. Fujimoto, S. J. Kim, E. F. Wawrousek, I. Gery; Homeostatic Activation Triggers Pathogenicity in Naive T-Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2644.
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Lymphocytes that recognize self-antigens are present in healthy individuals in a "resting" state. If activated, they may invade target tissues and cause pathogenic autoimmunity. One mechanism thought to be responsible for this activation of naive lymphocytes is homeostatic proliferation, in which T-cell loss, or lymphopenia stimulates expansion of T-cells as a compensatory mechanism to restore the T-cell pool. In support of this notion, a number of studies have demonstrated an association between homeostatic expansion and the development of various autoimmune disorders. Here, we investigated whether homeostatic proliferation could activate non-pathogenic tissue-specific naive T-cells and convert them into inflammation-inducing effector cells in vivo.
In the experimental system, naive CD4+ cells were isolated from hen egg lysozyme (HEL) -specific TCR transgenic (Tg) mice and injected into recipient mice expressing HEL under control of the rhodopsin (rHEL-Tg), or alpha A crystallin promoter (aHEL-Tg). No inflammation develops in the recipient mice, even following injection of HEL, unless the naive CD4 cells are activated, thus providing a system to examine the capacity of various treatments to activate naive T-cells that produce pathogenic autoimmunity. The treatments used were lymphopenia, caused by sublethal irradiation (450 Rad), or treatment with toll-like receptor (TLR) ligands, endotoxin, or CpG oligodeoxynucleotide. Development of ocular inflammation was determined histologically.
No changes were detected in control mice injected with naive CD4 cells, whereas ocular inflammation did develop in recipient mice that also received irradiation. The histological changes were more apparent in rHEL-Tg than in aHEL-Tg recipient mice. Moreover, these changes were enhanced by treatment of the recipients with HEL. Treatment of the recipient mice with TLR ligands triggered ocular inflammation, but the combination of irradiation and treatment with TLR ligands did not result in a synergistic increase in severity.
Our data support the notion that lymphopenia-induced homeostatic expansion of T-cells is a process that promotes autoimmunity by stimulating self-specific naive T-cells to become immunopathogenic and to initiate pathogenic autoimmunity. Our adoptive transfer system offers a novel assay to examine the compensatory mechanism of homeostatic proliferation in lymphopenic conditions that can lead to pathogenic autoimmunity.
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