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4 Integrins Regulate Independent Pathways of T Lymphocyte Recruitment in the Pulmonary Immune Response1 ,2
,
*
Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109;
Department of Internal Medicine (Pulmonary and Critical Care Medicine Division), University of Michigan Medical Center, and the Pulmonary and Critical Care Medicine Section, Department of Veterans Affairs Medical Center, Ann Arbor, MI 48105;
Howard Hughes Medical Research Institute, Ann Arbor, MI 48109; and
§
Athena Neurosciences, South San Francisco, CA 94080
The cell adhesion molecules (CAMs) required for T lymphocyte
recruitment during pulmonary immune responses have not been defined.
Our laboratories recently reported that intratracheal (IT) challenge of
sensitized mice with SRBC induced prolonged expression of vascular
P-selectin, E-selectin, and VCAM-1, particularly in areas of
mononuclear leukocyte infiltration. A surge in the number of
circulating T lymphocytes expressing selectin ligands preceded the peak
accumulation of T cells in the lung. In addition, a significant
percentage of the T cells recovered from the lung expressed selectin
ligands as well. The current study demonstrates that cultured T
lymphoblasts use both selectin ligands and 
4 integrins
to enter the airspace and interstitium during the response to SRBC.
Fluorescently labeled T lymphoblasts, derived via activation on CD3 and
growth in low dose IL-2, showed inflammation-specific recruitment into
lungs harvested 24 h after cell infusion. Their flux paralleled
the accumulation of host lymphocytes in the lung, with both peaking 2
to 4 days after SRBC challenge. Trafficking studies conducted over a
24-h period during peak lymphocyte accumulation in the lungs revealed
preferential recruitment of labeled T lymphoblasts expressing P- and
E-selectin ligands. In addition, mAb blockade of the 4
integrins and targeted deletion of an (1,3)fucosyltransferase
essential for selectin ligand synthesis each reduced labeled T
lymphoblast trafficking to a significant degree. Furthermore,
4 integrin blockade reduced the trafficking of the
selectin ligand-deficient cells into the airspace, confirming that its
contribution is in part independent from the vascular selectins. These
findings imply that both selectin ligands and 4
integrins participate in T lymphoblast recruitment during the pulmonary
immune response to IT SRBC.
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