Biomedical subjects

L Henault

Publications and source records attributed to L Henault.

4 recordsLinked to original sources

PubMed2000

Alpha4beta1-integrin activation is necessary for high-efficiency T-cell subset interactions with VCAM-1 under flow.

OBJECTIVE: The purpose of this study was to examine the relationship between alpha4beta1-integrin state of activation on CD4+ T-cell subsets and their adhesive interaction to VCAM-1 under flow. METHODS: Human CD4+ memory and naive T-cells were freshly isolated and effector-helper T-cell subsets. Th1 and Th2 cells, were differentiated in vitro from CD4+ naive T-cells. The expression of activation/ligand induced epitopes on beta1-integrins of each T-cell subset was assessed using mAb HUTS21 and mAb 15/7. T-cell subsets attachment and rolling on VCAM-1 was determined under defined flow conditions and the rates of attachment (ka), accumulation, and instantaneous rolling velocities were correlated to their beta1-integrin activation epitope expression. RESULTS: A subset of memory T-cells constitutively express activation/ligand induced epitopes on beta1-integrins recognized by mAb HUTS21 and 15/7, whereas expression levels on naive T-cells is low or not detectable. Consistent with an activated phenotype, memory T-cells exhibit significantly higher rates of attachment and accumulation on VCAM-1 under flow as compared to naive T-cells. Interestingly, the expression of activation/ligand induced epitopes on beta1-integrins on Th2 cells and the ability of these cells to interact with VCAM-1 are comparable to memory T-cells. In contrast, Th1 cells did not interact as efficiently with VCAM-1, which correlated with lower expression of activation/ligand induced epitopes on these cells. VCAM-1 interactions are inhibited completely by pretreatment of the T-cells with blocking mAb to alpha4-integrins or beta1-integrins, indicating that alpha4beta1 is the predominant T-cell integrin involved. CONCLUSIONS: Memory T-cells express constitutively active alpha4beta1-integrins, as compared to naive T-cells, which mediate high rates of initial attachment and sustained high-affinity adhesive interactions with VCAM-1 under flow conditions in vitro. Similarly, in vitro differentiated Th2 cells but not Th1 cells, which also express elevated levels of activated alpha4beta1-integrins, are capable of sustaining high-affinity adhesive interactions with VCAM-1. The differences observed in beta1-integrin activation on T-cell subsets may underlie selective recruitment patterns of T-cell subsets in vivo.

Cell Adhesion↗

PubMed1999

Expression of functional selectin ligands on Th cells is differentially regulated by IL-12 and IL-4.

Immune responses may be qualitatively distinct depending on whether Th1 or Th2 cells predominate at the site of Ag exposure. T cell subset-specific expression of ligands for vascular selectins may underlie the distinct patterns of recruitment of Th1 or Th2 cells to peripheral inflammatory sites. Here we examine the regulation of selectin ligand expression during murine T helper cell differentiation. Large numbers of Th1 cells interacted with E- and P-selectin under defined flow conditions, while few Th2 and no naive T cells interacted. Th1 cells also expressed more fucosyltransferase VII mRNA than naive or Th2 cells. IL-12 induced expression of P-selectin ligands on Ag-activated naive T cells, even in the presence of IL-4, and on established Th2 cells restimulated in the presence of IL-12 and IFN-gamma. In contrast, Ag stimulation alone induced only E-selectin ligand. Interestingly, restimulation of established Th2 cells in the presence of IL-12 and IFN-gamma induced expression of P-selectin ligands but not E-selectin ligands; IFN-gamma alone did not enhance expression of either selectin ligand. In summary, functional P- and E-selectin ligands are expressed on most Th1 cells, few Th2 cells, but not naive T cells. Furthermore, selectin ligand expression is regulated by the cytokine milieu during T cell differentiation. IL-12 induces P-selectin ligand, while IL-4 plays a dominant role in down-regulating E-selectin ligand.

Animals↗

PubMed1998

Endothelial antigen presentation: stimulation of previously activated but not naïve TCR-transgenic mouse T cells.

In vitro experiments have shown that endothelial cells can function as antigen-presenting cells to CD4(+) T lymphocytes. The studies presented here address the question of whether naïve versus previously activated CD4(+) helper T cells differ in their responses to endothelial antigen presentation. TCR-transgenic mice were used as a source of naive T cells of defined antigen specificity. These cells were stimulated in vitro with antigen and splenic antigen-presenting cells to generate populations of T lymphocytes with a previously activated/memory phenotype. Two different types of mouse endothelial cells were used as antigen-presenting cells, including the SVEC4-10 line derived from lymph node endothelium and primary murine pulmonary microvascular endothelium. Monolayer cultures of both types of endothelium were capable of antigen-dependent stimulation of previously activated TCR-transgenic CD4(+) cells. In contrast, neither endothelial type could activate naïve CD4(+) T cells. When costimulatory signals were provided in trans by the addition of MHC-mismatched mouse spleen cells, activation of naïve T cells by endothelial antigen presentation could be demonstrated. The expression of ICAM-1 or VCAM-1 on the endothelial cells was not sufficient to activate naïve T cells. Furthermore, the mouse lung endothelium constitutively expresses B7-1, and therefore, the inability of endothelium to stimulate naïve T cells could not be attributed to a lack of CD28-ligands. These studies suggest that the potential role of endothelial antigen presentation in immune responses is restricted to promoting responses by T cells which have previously encountered antigen presented by other antigen-presenting cells.

Animals↗

PubMed1997

CD45RA-RO+ (memory) but not CD45RA+RO- (naive) T cells roll efficiently on E- and P-selectin and vascular cell adhesion molecule-1 under flow.

This study examines the molecular mechanisms that underlie the observed preferential interactions of memory vs naive T cells with activated vascular endothelium. Many more CD4+ CD45RO+ (memory) cells adhered to 6-h TNF-alpha-activated human umbilical vein endothelium under flow than CD4+CD45RA+ (naive) cells. Adhesion studies were performed using Chinese hamster ovary (CHO) cell monolayers expressing human E- or P-selectin (CHO-E and CHO-P, respectively) or with soluble vascular cell adhesion molecule-1 (VCAM-1)-coated glass surfaces. Under flow at 1.8 dynes/cm2, RO+ T cells rolled extensively at low velocity on both CHO-P and CHO-E monolayers and VCAM-1, whereas very few RA+ T cells interacted with these surfaces. VCAM-1-dependent rolling was blocked completely by anti-very late Ag-4 (VLA-4) Abs. Purified CD4+RA+ T cells could be converted to RO+ cells by mitogen stimulation and 7-day culture in vitro, and this correlated with the acquisition of the ability to roll on E- or P-selectin, but not on VCAM-1 under flow. In summary, these data indicate that CD45RO+ cells interact with E- and P-selectins and VCAM-1 much more effectively than do CD45RA+ cells under flow conditions, and these adhesion pathways may contribute, either individually or in combination, to the preferential recruitment of memory T cells to peripheral sites of inflammation.

Animals↗