Impaired responsiveness to T-cell receptor stimulation and defective negative selection of thymocytes in CCR7-deficient mice.

The chemokine receptor CCR7 has been implicated in maintenance of thymus morphology and establishment of tolerance to self-antigens. In this study, we provide direct evidence that negative selection of maturing thymocytes is defective in CCR7-deficent mice. Impaired negative selection was observed after TCR/CD3 complex stimulation in vivo as well as in vitro and was prominent in both double-positive and semimature single positive cells (CD4(+)CD8(-)CD24(high)). It is noteworthy that thymocytes of CCR7(-/-) mice display defective negative selection in response to endogenous superantigens, demonstrating that the defect also occurs under physiological conditions. Disturbed negative selection was correlated with delayed activation kinetics and decreased calcium flux response of CCR7(-/-) thymocytes after in vitro TCR/CD3 stimulation, suggesting that an impaired response of CCR7(-/-) thymocytes via TCR-mediated signaling is responsible for defective negative selection in these mice.

Generalized multi-organ autoimmunity in CCR7-deficient mice.

Development of autoimmunity is a multi-factorial process involving genetic predisposition as well as environmental and stochastic factors. Although the mechanisms responsible for the initiation of autoimmunity remain only partially understood, several studies have demonstrated that genetic predisposition plays a major role in this process. In the present study, we analyzed the influence of CCR7 signaling in the development of autoimmunity, because this chemokine receptor is essentially involved in the functional organization of thymus architecture. We demonstrate that CCR7-deficient mice are prone to develop generalized multi-organ autoimmunity. The autoimmune phenotype of CCR7-/- mice encompasses the presence of lymphocyte infiltrates in several peripheral organs, circulating autoantibodies against a multitude of tissue-specific antigens and IgG deposition on renal glomeruli. Additionally, CCR7-deficient mice show increased susceptibility to streptozotocin-induced diabetes and spontaneously display signs of chronic autoimmune renal disease. Thus, this study identifies CCR7 as a genetic factor involved in the regulation of autoimmunity.