Summary: CD4⁺ CD25⁺ regulatory T (Treg) cells play an important role in the control of the immune system by suppressing the proliferation of effector cells, thereby preventing autoreactive, unnecessary or inconvenient responses. Recently, it has been shown that the number of Treg cells increases during pregnancy, a period with high serum levels of female sex hormones. Oestrogen replacement therapy has been reported to alleviate the symptoms of autoimmune diseases, yet the cellular and molecular mechanisms involved are not fully understood. Here, we show that physiological doses of oestradiol (E2) found during pregnancy, combined with activation through CD3/CD28 engagement, promoted the proliferation of Treg cells without altering their suppressive phenotype. Enhanced suppression was detected when Treg cells were pretreated with the hormone as well as when both cell subpopulations (Treg and T effector) were exposed to E2 throughout the experiment. Together, these data suggest that when combined with an activating stimulus, E2 can modulate the function of human Treg cells by regulating their numbers, and highlight a potential use of E2, or its analogs, to manipulate Treg function.

Heat shock protein 70 (Hsp70) is an intracellular chaperone protein with regulatory and cytoprotective functions. Hsp70 can also be found in the extracellular milieu, as a result of active secretion or passive release from damaged cells. The role of extracellular Hsp70 is not fully understood. Some studies report that it activates monocytes, macrophages and dendritic cells through innate immune receptors (such as Toll-like receptors, TLRs), while others report that Hsp70 is a negative regulator of the inflammatory response. In order to address this apparent inconsistency, in this study we evaluated the response of human monocytes to a highly purified recombinant Hsp70.

Dermaseptin S9 (Drs S9), GLRSKIWLWVLLMIWQESNKFKKM, isolated from frog skin, does not resemble any of the cationic and amphipathic antimicrobial peptides identified to date, having a highly hydrophobic core sequence flanked at either side by cationic termini. Previous studies [Lequin O, Ladram A, Chabbert A, Bruston F, Convert O, Vanhoye D, Chassaing G, Nicolas P & Amiche M (2006) Biochemistry45, 468–480] demonstrated that this peptide adopted a non‐amphipathic α‐helical conformation in trifluoroethanol/water mixtures, but was highly aggregated in aqueous solutions and in the presence of sodium dodecyl sulfate micelles. Circular dichroism, FTIR and attenuated total reflectance FTIR spectroscopies, combined with a surface plasmon resonance study, show that Drs S9 forms stable and ordered β‐sheet aggregates in aqueous buffers or when bound to anionic or zwitterionic phospholipid vesicles. These structures slowly assembled into amyloid‐like fibrils in aqueous environments via spherical intermediates, as revealed by electron microscopy and Congo red staining. Drs S9 induced the directional migration of neutrophils, T lymphocytes and monocytes. Interestingly, the antimicrobial and chemotactic activities of Drs S9 are modulated by its amyloid‐like properties. Whereas spherical oligomers of Drs S9 exhibit antimicrobial activity, the soluble, weakly self‐associated forms of Drs S9 act on human leukocytes to promote chemotaxis and/or immunological response activation in the same range of concentration as amyloidogenic peptides Aβ(1–42), the most fibrillogenic isoform of amyloid beta peptides, and the prion peptide PrP(106–126).

An important step of innate immune response is the recruitment of polymorphonuclear leukocytes (PMN) to injured tissues through chemotactic molecules. Galectins, a family of endogenous lectins, participate in numerous functions such as lymphoid cell migration, homing, cell–cell and cell–matrix interactions. Particularly, galectin-3 (Gal-3) and -9 have been implicated in the modulation of acute and chronic inflammation by inducing the directional migration of monocytes/macrophages and eosinophils, whereas Gal-1 is considered to function as an anti-inflammatory molecule, capable of inhibiting the influx of PMN to the site of injury. In this study, we assessed the effect of Gal-1 on neutrophil recruitment, in the absence of additional inflammatory insults. Contrasting with its capacity to inhibit cell trafficking and modulate the release of mediators described in models of acute inflammation and autoimmunity, we evidenced that Gal-1 has the capacity to induce neutrophil migration both in vitro and in vivo. This effect is not mediated through a G-protein-coupled receptor but potentially through the sialoglycoprotein CD43, via carbohydrate binding and through the p38 mitogen-activated protein kinase pathway. These results suggest a novel biological function for CD43 on neutrophils and highlight that depending on the environment, Gal-1 can act either as chemoattractant or, as a molecule that negatively regulates migration under acute inflammatory conditions, underscoring the potential of Gal-1 as a target for innovative drug development.

CD43, the most abundant membrane protein of T lymphocytes, is able to initiate signals that lead to Ca²⁺ mobilization and interleukin-2 production, yet the molecular events involved in signal transduction pathway of the CD43 molecule are only beginning to be understood. We have shown recently that cross-linking CD43 on the cell surface of human T lymphocytes with the anti-CD43 monoclonal antibody L10 leads to CD43-Fyn kinase interactions and to Fyn phosphorylation on tyrosine residues. This interaction seems to be mediated by the SH3 domain of Fyn and a proline-rich sequence located in the cytoplasmic domain of CD43. Here we show that CD43-specific activation of human T lymphocytes induced tyrosine phosphorylation of the adaptor protein Shc and of the guanine exchange factor Vav, as well as the formation of a macromolecular complex that comprises Shc, GRB2, and Vav. CD43 ligation resulted in enhanced formation of Vav·SLP-76 complexes and in the activation and nuclear translocation of ERK2. Cross-linking of the CD43 molecule in 3T3-CD43⁺ cells induced luciferase activity from a construct under the control of the Fos serum responsive element. Altogether, these data suggest that the mitogen-activated protein kinase pathway is involved in CD43-dependent interleukin-2 gene expression.