THE ROUTE OF ANTIGEN ENTRY DETERMINES THE REQUIREMENT FOR L-SELECTIN DURING IMMUNE-RESPONSES

L-selectin, an adhesion molecule constitutively expressed on leukocyte s, is important for primary adhesion and extravasation of lymphocytes at specialized high endothelial venules within lymph nodes and other l eukocytes at sites of inflammation. We have generated L-selectin-defic ient mice by targeted disruption, and have confirmed a previously repo rted phenotype which includes strikingly impaired contact hypersensiti vity (CHS) responses to reactive haptens (Tedder, T.F., D.A. Steeber, and P. Pizcueta. 1995. J. Exp. Med. 181:2259-2264; Xu, J.C., I.S. Grew al, G.P. Geba, and R.A. Flavell. 1996. 183:589-598.). Since the mechan ism of this impairment has not been clarified, we sought to define the stage(s) at which the CHS response is affected in L-selectin-deficien t mice. We show that epidermal Langerhans cells in L-selectin-deficien t mice are normal in number, migrate to peripheral lymph nodes appropr iately, and are functional in presenting allogeneic and haptenic antig ens. Moreover, T cells, as well as neutrophil and monocyte effector po pulations, are fully capable of entry into the inflamed skin sites in the absence of L-selectin. Thus, antigen presentation and effector mec hanisms are intact in L-selectin deficient mice. In contrast, virtuall y no antigen-specific T cells can be found within draining peripheral nodes after a contact challenge, suggesting that the defect resides pr imarily in the inability of antigen-specific T cells to home to and be activated in these nodes. Indeed, L-selectin-deficient mice mount com pletely normal CHS responses when alternate routes of immunization are used. These studies pinpoint the lesion in CHS to a discrete stage of the afferent limb of the response, clarify the role of L-selectin on effector populations, and illustrate the critical importance of the ro ute of antigen entry to the successful execution of an immune response .