There is growing evidence that apoptotic neutrophils have an active role to play in the regulation and resolution of inflammation following phagocytosis by macrophages and dendritic cells. However, their influence on activated blood monocytes, freshly recruited to sites of inflammation, has not been defined. In this work, we examined the effect of apoptotic neutrophils on cytokine production by LPS-activated monocytes. Monocytes stimulated with LPS in the presence of apoptotic neutrophils for 18 h elicited an immunosuppressive cytokine response, with enhanced IL-10 and TGF-β production and only minimal TNF-α and IL-1β cytokine production. Time-kinetic studies demonstrated that IL-10 production was markedly accelerated in the presence of apoptotic neutrophils, whereas there was a sustained reduction in the production of TNF-α and IL-1β. This suppression of proinflammatory production was not reversible by depletion of IL-10 or TGF-β or by addition of exogenous IFN-γ. It was demonstrated, using Transwell experiments, that monocyte-apoptotic cell contact was required for induction of the immunosuppressive monocyte response. The response of monocytes contrasted with that of human monocyte-derived macrophages in which there was a reduction in IL-10 production. We conclude from these data that interaction between activated monocytes and apoptotic neutrophils creates a unique response, which changes an activated monocyte from being a promoter of the inflammatory cascade into a cell primed to deactivate itself and other cells.
This study shows that, in humans at birth, circulating T cells represent recent thymic emigrants (RTEs) as reflected in their high level of expression of TCR excision circles. RTEs express “thymocyte-like” characteristics with regard to rapid rate of apoptosis. In the presence of common γ-chain cytokines, in particular IL-7, they show enhanced potential to survive, entry into cell cycle, and proliferation. Although common γ-chain cytokines were also potent antiapoptotic stimuli for mature adult-derived naive CD4+CD45RA+ T cells, these cells were refractory to IL-7-induced expansion in vitro. RTEs cultured with IL-7 could not reinduce recombination-activating gene-2 gene expression in vitro. These data suggest that postthymic naive T cells in the periphery during early life are at a unique stage in ontogeny as RTEs, during which they can undergo homeostatic regulation including expansion and survival in an Ag-independent manner while maintaining their preselected TCR repertoire.
In conditions of optimal priming, the neonate possess competency to mount quantitatively adult-like responses. Vaccine formulations containing sufficiently potent adjuvants may overcome the neonates’ natural tendency for immunosuppression and provoke a similarly robust immune response. TLR expression on T cells represents the possibility of directly enhancing T cell immunity. We examined the ex vivo responsiveness of highly purified human cord blood-derived CD8+ T cells to direct TLR ligation by a repertoire of TLR agonists. In concert with TCR stimulation, only Pam3Cys (palmitoyl-3-Cys-Ser-(Lys)4) and flagellin monomers significantly enhanced proliferation, CD25+ expression, IL-2, IFN-γ, TNF-α, and intracellular granzyme B expression. TLR2 and TLR5 mRNA was detected in the CD8+ T cells. Blocking studies confirmed that the increase in IFN-γ production was by the direct triggering of surface TLR2 or TLR5. The simultaneous exposure of CD8+ T cells to both TLR agonists had an additive effect on IFN-γ production. These data suggest that a combination of the two TLR ligands would be a potent T cell adjuvant. This may represent a new approach to TLR agonist-based adjuvant design for future human neonatal vaccination strategies requiring a CD8+ component.
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