Adenoviral-Mediated Gene Transfer of Lymphotactin to the Lungs of Mice and Rats Results in Infiltration and Direct Accumulation of CD4 +,CD8 +,and NK Cells

Abstract

Chemokines are small 8-12-kDa chemotactic cytokines that were initially characterized for their ability to control leukocyte trafficking and, to a lesser extent, leukocyte function. Lymphotactin was first described as a T lymphocyte-specific chemotactic factor. However, it has since been shown to also be a potent attractant for natural killer (NK) cells. The chemotactic properties of lymphotactin suggested from in vitro data prompted us to study the in vivo activity of this chemokine. We constructed an adenovirus vector expressing murine lymphotactin (Ad mLym) and used this construct to overexpress lymphotactin in the lungs of both mice and rats, with similar outcomes. In brief, the accumulation of CD4⁺ and CD8⁺ T cells and NK cells surprisingly demonstrated slow kinetics, uncharacteristic of the chemoattractant potential seen with other chemokines. Lymphocyte accumulation in the lung was not evident prior to 24 h after gene transfer and reached a peak by day 7 in mice and day 14 in rats. Interestingly, the cellular infiltrate recruited to the lung by lymphotactin was a heterogeneous mixture of lymphocytes, monocytes, and neutrophils. Administration of Ad mLym to BALB/c SCID mice demonstrated that the presence of monocytes and neutrophils in the bronchoalveolar lavage (BAL) of wild-type BALB/c mice was likely due to the action of lymphotactin on lymphocytes. These findings extend the previousin vitro findings on the activity of lymphotactin and provide a model for studying the local effects of overexpressing chemokines in various tissues in vivo.