Motility of IL-2-stimulated lymphocytes in neutral and acidified extracellular matrix.
The migration of lymphocytes through extracellular matrix (ECM) is an essential feature of the infiltration process. In the course of their extravasation into poorly perfused neoplastic lesions, lymphocytes often encounter regions of acidified ECM. This study was designed to determine whether lymphocyte adherence and motility in ECM are influenced by ambient pH. Murine splenic lymphocytes, activated by culture with high-titer IL-2, were allowed to migrate into three-dimensional gels of Type I collagen, a major component of interstitial stroma, or into Matrigel, a basement membrane model. After 18 hr at pH 7.1, the leading cell front traveled a mean distance of approx 475 microM into Type I collagen gel. Approx 50% of the cells remained nonadherent, 25% adhered to the gel surface, and 25% were motile (penetrated beneath the surface). At pH 6.7, the leading-front distance increased significantly, by a factor of 1.4X, but there was little change in the proportion of cells exhibiting nonadherence, surface adherence, or motility. The relative motilities of CD3+ and AsGM1+ subsets were also unaltered. It therefore appears that acidification of collagen matrix increases the locomotory activity of motile lymphocytes, but causes little recruitment of nonmotile lymphocytes into the motile pool. Similar results were obtained in experiments with Matrigel. The increased motility observed at pH 6.7 did not reflect breakdown or relaxation of matrix lattices, as measured by the passive diffusion of latex beads of defined diameter. Preincubation of lymphocytes at pH 6.7 did not alter their subsequent motility in pH 7.1 gels. The findings establish ambient pH as a microenvironmental variable which can influence lymphocyte migration through ECM. The weak acidity characteristic of certain tumor microenvironments may be a factor which encourages lymphocyte infiltration through tissue matrix. Treatments which alter intratumor pH could potentially be used to manipulate the infiltration process for immunotherapeutic benefit.
Ratner
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Department of Immunology, Michigan Cancer Foundation, Detroit 48201-1379.
D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D003094:Collagen; D004338:Drug Combinations; D005109:Extracellular Matrix / Q000737:chemistry; D005782:Gels; D006863:Hydrogen-Ion Concentration; D007376:Interleukin-2 / Q000494:pharmacology*; D007797:Laminin; D008214:Lymphocytes / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D011509:Proteoglycans; D013154:Spleen / Q000166:cytology
D004338:Drug Combinations; D005782:Gels; D007376:Interleukin-2; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen