Theoretical Model for Cellular Shapes Driven by Protrusive and Adhesive Forces

The forces that arise from the actin cytoskeleton play a crucial role in determining the cell shape. These include protrusive forces due to actin polymerization and adhesion to the external matrix. We present here a theoretical model for the cellular shapes resulting from the feedback between the membrane shape and the forces acting on the membrane, mediated by curvature-sensitive membrane complexes of a convex shape. In previous theoretical studies we have investigated the regimes of linear instability where spontaneous formation of cellular protrusions is initiated. Here we calculate the evolution of a two dimensional cell contour beyond the linear regime and determine the final steady-state shapes arising within the model. We find that shapes driven by adhesion or by actin polymerization (lamellipodia) have very different morphologies, as observed in cells. Furthermore, we find that as the strength of the protrusive forces diminish, the system approaches a stabilization of a periodic pattern of protrusions. This result can provide an explanation for a number of puzzling experimental observations regarding cellular shape dependence on the properties of the extra-cellular matrix

Differential Expression of Alpha 4 Integrins on Effector Memory T Helper Cells during Bordetella Infections. Delayed Responses in Bordetella pertussis

Bordetella pertussis (B. pertussis) is the causative agent of whooping cough, a respiratory disease that is reemerging worldwide. Mechanisms of selective lymphocyte trafficking to the airways are likely to be critical in the immune response to this pathogen. We compared murine infection by B. pertussis, B. parapertussis, and a pertussis toxin-deleted B. pertussis mutant (BpΔPTX) to test the hypothesis that effector memory T-helper cells (emTh) display an altered pattern of trafficking receptor expression in B. pertussis infection due to a defect in imprinting. Increased cell recruitment to the lungs at 5 days post infection (p.i.) with B. parapertussis, and to a lesser extent with BpΔPTX, coincided with an increased frequency of circulating emTh cells expressing the mucosal-associated trafficking receptors α4β7 and α4β1 while a reduced population of these cells was observed in B. pertussis infection. These cells were highly evident in the blood and lungs in B. pertussis infection only at 25 days p.i. when B. parapertussis and BpΔPTX infections were resolved. Although at 5 days p.i., an equally high percentage of lung dendritic cells (DCs) from all infections expressed maturation markers, this expression persisted only in B. pertussis infection at 25 days p.i. Furthermore, at 5 days p.i with B. pertussis, lung DCs migration to draining lymph nodes may be compromised as evidenced by decreased frequency of CCR7+ DCs, inhibited CCR7-mediated in vitro migration, and fewer DCs in lung draining lymph nodes. Lastly, a reduced frequency of allogeneic CD4+ cells expressing α4β1 was detected following co-culture with lung DCs from B. pertussis-infected mice, suggesting a defect in DC imprinting in comparison to the other infection groups. The findings in this study suggest that B. pertussis may interfere with imprinting of lung-associated trafficking receptors on T lymphocytes leading to extended survival in the host and a prolonged course of disease

Antigen receptor V-segment usage in mucosal T cells

In the accepted model of lymphocyte intestinal homing, naïve T cells recirculate via organized lymphoid tissues, whilst induced effector/memory cells home to the intestinal mucosa. In order to assess the T-cell-receptor repertoire in the intestine and gut-associated lymphoid tissue (GALT), spectratyping was performed on the proximal and the distal intestine, spleen and mesenteric lymph node tissue from six PVG rats. The products were analysed with an automated sequencer and statistical analyses were performed with hierarchical cluster analysis. This demonstrated the presence of a restricted T-cell repertoire in the small intestine compared with that in the mesenteric lymph nodes and the spleen. It also demonstrated marked differences in repertoire between individual, fully inbred rats maintained under apparently identical conditions in the same cage and fed identical diets. In addition, this work demonstrated marked differences between repertoires in the proximal and the distal intestine. Such marked differences are likely to reflect the end result of increasing divergence over time produced by relatively subtle effects of environment and antigenic load. Equally, marked differences in repertoire between small intestinal segments within individual rats indicate selective recruitment or retention of specific clones, presumably antigen-driven

Quantitative and functional characteristics of intestinal-homing memory T cells: analysis of Crohn's disease patients and healthy controls

Circulating memory T cells can be subdivided on the basis of β7 integrin expression. The β7(+) population contains cells primed in the intestine capable of homing back to the gut. We hypothesized that cytokine production by β7(+) memory T cells reflects the specialized mucosal compartment in which they were primed. Flow cytometry of whole blood was used to assess numbers of β7(+) (β7(hi) and β7(int)) and β7(–) memory T cells and their production of Th1 and regulatory cytokines in healthy controls and Crohn's disease patients. In controls, β7(+) and β7(–) memory T cells displayed a similar qualitative profile of cytokine production but the β7(+) population was enriched for cytokine-producing effector cells. In addition, the β7(hi) population contained more cytokine-producing cells than the β7(int) population, suggesting a gradient of cytokine production based on β7 integrin expression. In active Crohn's disease, there was altered expression of β7 integrin with a decrease in intestinal-homing memory T cells and an increase in systemic memory T cells. Furthermore, there was a selective loss of IL-10 and increase in TGF-β in both β7(+) and β7(–) memory T cell subsets which may contribute to the pathogenesis of the inflammatory process in Crohn's disease

Preferential production of interferon-γ by CD4(+) T cells expressing the homing receptor integrin α(4)/β(7)

Recent studies indicate that T helper type 1 (Th1) and 2 (Th2) lymphocytes differ in their expression of molecules that control T-cell migration, including adhesion molecules and chemokine receptors. We investigated the relationship between cytokine production and expression of the homing receptor integrin α(4)/β(7) on T cells. We began by analysing cytokine production by human CD4(+) CD45RA(–) memory/effector T cells following brief (4 hr) stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. α(4)/ [Image: see text] CD4(+) T cells were more likely to produce the Th1 cytokine interferon-γ (IFN-γ) than were α(4)/β(7)(−) CD4(+) T cells in all six subjects studied. In contrast, production of the Th2 cytokine interleukin-4 (IL-4) was similar on α(4)/ [Image: see text] and α(4)/β(7)(−) CD4(+) T cells. In addition, we found that human CD4(+) CD45RA(–) T cells that adhered to the α(4)/β(7) ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) had a greater capacity to produce IFN-γ than did non-adherent cells, suggesting that the association between α(4)/β(7) expression and IFN-γ production has functional significance. These results suggested that primary activation under Th1-promoting conditions might favour expression of α(4)/β(7). We directly examined this possibility, and found that naïve murine CD4(+) T cells activated under Th1-promoting conditions expressed higher levels of α(4)/β(7) compared to cells activated under Th2-promoting conditions. The association between α(4)/β(7) expression and IFN-γ production by CD4(+) T cells may help to determine the cytokine balance when MAdCAM-1 is expressed at sites of inflammation in the intestine or elsewhere