Hiroaki Takimoto

Platelet/endothelial cell adhesion molecule-1 (PECAM-1; CD31), a member of the Ig superfamily, is expressed strongly at endothelial cell-cell junctions, on platelets, and on most leukocytes. CD31 has been postulated to play a role in vasculogenesis and angiogenesis, and has been implicated as a key mediator of the transendothelial migration of leukocytes. To further define the physiologic role of CD31, we used targeted gene disruption of the CD31 gene in embryonic stem cells to generate CD31-deficient mice. CD31-deficient mice (CD31KO) are viable and born at the expected Mendelian frequency, remain healthy, and exhibit no obvious vascular developmental defects. In response to inflammatory challenge, polymorphonuclear leukocytes of CD31KO mice are arrested between the vascular endothelium and the basement membrane of inflammatory site mesenteric microvessels, confirming a role for CD31 in the migration of neutrophils through the subendothelial extracellular matrix. Normal numbers of leukocytes are recovered from inflammatory sites in CD31KO mice, however, suggesting that the defect in leukocyte migration across basal lamina observed in the absence of CD31 may be compensated for by the use of other adhesion molecules, or possibly an increased rate of migration. Homing of T lymphocytes in vivo is normal, and CD31KO mice are able to mount a cutaneous hypersensitivity response normally. In addition, CD31-mediated homophilic adhesion does not appear to play a role in platelet aggregation in vitro. This study provides genetic evidence that CD31 is involved in transbasement membrane migration, but does not play an obligatory role in either vascular development or leukocyte migration.

The interleukin-2 receptor beta chain (IL-2R beta) is expressed on a variety of hematopoietic cell types, including natural killer (NK) cells and nonconventional T lymphocyte subsets such as intestinal intraepithelial lymphocytes (IEL). However, the importance of IL-2R beta-mediated signaling in the growth and development of these cells has yet to be clearly established. We have investigated IEL and NK cells in mice deficient for IL-2R beta and describe here striking defects in the development of these cells. IL-2R beta-/- mice exhibited an abnormal IEL cell population, characterized by a dramatic reduction in T cell receptor alpha beta CD8 alpha alpha and T cell receptor gamma delta lymphocytes. This selective decrease indicates that IEL can be classified into those whose development and/or differentiation is dependent on IL-2R beta function and those for which IL-2R beta-mediated signaling is not essential. NK cell development was also found to be disrupted in IL-2R beta-deficient mice, characterized by a reduction in NK1.1+CD3- cells in the peripheral circulation and an absence of NK cytotoxic activity in vitro. The dependence of NK cells and certain subclasses of IEL cells on IL-2R beta expression points to an essential role for signaling through this receptor, presumably by IL-2 and/or IL-15, in the development of lymphocyte-subsets of extrathymic origin.