Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.
Constitutive egress of bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) into the blood is a well-established phenomenon, but the ultimate fate and functional relevance of circulating HSPCs is largely unknown. We show that mouse thoracic duct (TD) lymph contains HSPCs that possess short- and long-term multilineage reconstitution capacity. TD-derived HSPCs originate in the BM, enter the blood, and traffic to multiple peripheral organs, where they reside for at least 36 hr before entering draining lymphatics to return to the blood and, eventually, the BM. HSPC egress from extramedullary tissues into lymph depends on sphingosine-1-phosphate receptors. Migratory HSPCs proliferate within extramedullary tissues and give rise to tissue-resident myeloid cells, preferentially dendritic cells. HSPC differentiation is amplified upon exposure to Toll-like receptor agonists. Thus, HSPCs can survey peripheral organs and can foster the local production of tissue-resident innate immune cells under both steady-state conditions and in response to inflammatory signals.
After homing to lymph nodes, CD8 + T cells are primed by dendritic cells (DCs) in three phases. During phase one, T cells undergo brief serial contacts with DCs for several hours, whereas phase two is characterized by stable T cell-DC interactions. We show here that the duration of phase one and T cell activation kinetics correlated inversely with the number of complexes of cognate peptide and major histocompatibility complex (pMHC) per DC and with the density of antigen-presenting DCs per lymph node. Very few pMHC complexes were necessary for the induction of full-fledged T cell activation and effector differentiation. However, neither T cell activation nor transition to phase two occurred below a threshold antigen dose determined in part by pMHC stability. Thus, phase one permits T cells to make integrated 'measurements' of antigen dose that determine subsequent T cell participation in immune responses.The naive T cell population expresses a broad array of unique T cell antigen receptors (TCRs), each with a discrete affinity for a given complex of cognate peptide and major histocompatibility complex (pMHC). Naive T cells constantly survey and sample antigenpresenting cells (APCs) in secondary lymphoid tissues in search of rare cognate pMHC complexes 1 . Due to the diversity of the TCR repertoire, only one in 1 × 10 5 to 1 × 10 6 T cells expresses a TCR with sufficient affinity for any given antigen to transmit an activating Correspondence should be addressed to U. H.v.A. (E-mail: uva@cbr.med.harvard.edu). Note: Supplementary information is available on the Nature Immunology website. AUTHOR CONTRIBUTIONSS.E.H. designed the study, did and analyzed experiments, and wrote the manuscript; U.H.v.A designed the study and wrote the manuscript; T.R.M., I.B.M., A.P., M.P.F., B.S. and T.J. did experiments; B.L. and H.C.W. provided reagents; and M.N.A., H.Z. and A.K.C. modeled the experimental data. COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/natureimmunology/.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript stimulus 2,3 . Activation of naive T cells also requires costimulatory and cytokine signals 4,5 , which are typically provided by mature dendritic cells (DCs) in secondary lymphoid tissues 6 . As they 'hunt' for their cognate antigen, naive T cells recirculate between the blood and lymph nodes and spend less than 1 d in any given secondary lymphoid tissue 1,7 . When T cells encounter antigen in the proper context, they become activated and upregulate the activation marker CD69, which causes their retention in lymph nodes 8 . The trapped cells proliferate and acquire effector functions. Effector cells egress from lymph nodes and travel to peripheral tissues to seek out cells presenting cognate antigen 9 .Although this chain of events is well establ...
We have used intravital microscopy to study physiologically perfused microvessels in murine bone marrow (BM). BM sinusoids and venules, but not adjacent bone vessels, supported rolling interactions of hematopoietic progenitor cells. Rolling did not involve L-selectin, but was partially reduced in wild-type mice treated with antibodies to P- or E-selectin and in mice that were deficient in these two selectins. Selectin-independent rolling was mediated by α4 integrins, which interacted with endothelial vascular cell adhesion molecule (VCAM)-1. Parallel contribution of the endothelial selectins and VCAM-1 is not known to direct blood cell trafficking to other noninflamed tissues. This combination of constitutively expressed adhesion molecules may thus constitute a BM-specific recruitment pathway for progenitor cells analogous to the vascular addressins that direct selective lymphocyte homing to lymphoid organs.
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