An in vitro model to assess the immunosuppressive effect of tick saliva on the mobilization of inflammatory monocyte-derived cells

Tick-borne pathogens cause potent infections. These pathogens benefit from molecules contained in tick saliva that have evolved to modulate host innate and adaptive immune responses. This is called "saliva-activated transmission" and enables tick-borne pathogens to evade host immune responses. Ticks feed on their host for relatively long periods; thus, mechanisms counteracting the inflammation-driven recruitment and activation of innate effector cells at the bite site, are an effective strategy to escape the immune response. Here, we developed an original in vitro model to evaluate and to characterize the immunomodulatory effects of tick saliva that prevent the establishment of a local inflammatory immune response. This model mimics the tick bite and enables the assessment of the effect of saliva on the inflammatory-associated dynamic recruitment of cells from the mononuclear phagocyte system. Using this model, we were able to recapitulate the dual effect of tick saliva on the mobilization of inflammatory monocyte-derived cells, i.e. (i) impaired recruitment of monocytes from the blood to the bite wound; and (ii) poor mobilization of monocyte-derived cells from the skin to the draining lymph node. This simple tool reconstitutes the effect of tick saliva in vivo, which we characterized in the mouse, and should enable the identification of important factors facilitating pathogen infection. Furthermore, this model may be applied to the characterization of any pathogen-derived immunosuppressive molecule affecting the establishment of the inflammatory immune response

Neonatal Colonisation Expands a Specific Intestinal Antigen-Presenting Cell Subset Prior to CD4 T-Cell Expansion, without Altering T-Cell Repertoire

Interactions between the early-life colonising intestinal microbiota and the developing immune system are critical in determining the nature of immune responses in later life. Studies in neonatal animals in which this interaction can be examined are central to understanding the mechanisms by which the microbiota impacts on immune development and to developing therapies based on manipulation of the microbiome. The inbred piglet model represents a system that is comparable to human neonates and allows for control of the impact of maternal factors. Here we show that colonisation with a defined microbiota produces expansion of mucosal plasma cells and of T-lymphocytes without altering the repertoire of alpha beta T-cells in the intestine. Importantly, this is preceded by microbially-induced expansion of a signal regulatory protein α-positive (SIRPα+) antigen-presenting cell subset, whilst SIRPα−CD11R1+ antigen-presenting cells (APCs) are unaffected by colonisation. The central role of intestinal APCs in the induction and maintenance of mucosal immunity implicates SIRPα+ antigen-presenting cells as orchestrators of early-life mucosal immune development

Enrichment for a SIRP negative dendritic cell subset in lymph draining the upper aero-digestive tract: potential implication for tolerance

International audienc

Etude de la présentation antigènique induite par voie conjonctivale chez le mouton

National audienc

Enrichment for a CD26(hi) SIRP- subset in lymph dendritic cells from the upper aero-digestive tract

International audienceDendritic cells (DC) have been reported to migrate in afferent lymph in the steady state. However, it is unknown whether DC traffic is modulated by the nature of the drained tissue. To analyze the influence of mucosal versus cutaneous microenvironments on the constitutive DC release, we exploited a novel technique of lymph cannulation in sheep, which allowed a comparison of afferent lymph DC migrating from the head mucosae [cervical DC (CerDC)] with DC migrating from skin [prescapular DC (PresDC)]. The migration rate was lower for CerDC than for PresDC. Compared with PresDC, CerDC contained a higher proportion of the CD26hi signal regulatory protein (SIRP)– DC subset. It is interesting that cytoplasmic apoptotic DNA as well as cytokeratin-positive inclusions were primarily detected among CD26hi SIRP– DC, an observation similar to that made in rats, which leads to the suggestion that this subset was involved in self-antigen presentation and tolerance induction. After the inoculation of cholera toxin (CT) onto the oro-nasal mucosae, migration of CD26hi SIRP– and CD26lo SIRP_ DC was accelerated in lymph, indicating that the effect of CT on DC mobilization is not subset-specific. Our results show that a mucosal environment influences DC output and the relative DC subset representation in lymph. This modulation of DC traffic to lymph nodes by mucosal surfaces is likely to affect the bias of the mucosal immune responses

Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Rα complexes

Cytotoxic lymphocytes such as natural killer (NK) and CD8 T cells play important roles in immunosurveillance by killing virally infected or malignant cells. The homeostatic cytokine, IL-15, promotes the development, function, and survival of NK and CD8 T cells. IL-15 is normally presented in trans as a surface complex with IL-15 receptor-alpha-chain (IL-15Rα) by dendritic cells (DCs) and monocytes. Signaling by IL-15 occurs via the IL-2/IL-15 receptor β-chain (CD122) which is expressed primarily by NK1.1+ cells and CD8 T cells. The use of preformed complexes of IL-15 with soluble IL-15Rα complexes to boost the effector function of CD122+ cytolytic lymphocytes such as NK and CD8 T cells has recently gained considerable attention. Here we describe the impact of transient and prolonged in vivo stimulation by IL-15/IL-15Rα complexes on NK and CD8 T cells. Whereas transitory stimulation increased the number of activated NK cells and significantly enhanced their effector function, prolonged stimulation by IL-15/IL-15Rα complexes led to a marked accumulation of mature NK cells with considerably impaired activation, cytotoxicity, and proliferative activity, and an altered balance of activating and inhibitory receptors. In contrast to NK cells, CD8 T cells exhibited an activated phenotype and robust T cell receptor stimulation and effector function upon chronic stimulation with IL-15/IL-15Rα complexes. Thus, prolonged stimulation with the strong activating signal leads to a preferential accrual of mature NK cells with altered activation and diminished functional capacity. These findings point to a negative feedback mechanism to preferentially counterbalance excessive NK cell activity and may have important implications for cytokine immunotherapy

A mouse model of latent tuberculosis infection to study intervention strategies to prevent reactivation

Infection with Mycobacterium tuberculosis (Mtb) is the leading cause of death in human immunodeficiency virus (HIV)+ individuals, particularly in Sub-Saharan Africa. Management of this deadly co-infection is a significant global health challenge that is exacerbated by the lack of efficient vaccines against both Mtb and HIV, as well as the lack of reliable and robust animal models for Mtb/HIV co-infection. Here we describe a tractable and reproducible mouse model to study the reactivation dynamics of latent Mtb infection following the loss of CD4+ T cells as it occurs in HIV-co-infected individuals. Whereas intradermally (i.d.) infected C57BL/6 mice contained Mtb within the local draining lymph nodes, depletion of CD4+ cells led to progressive systemic spread of the bacteria and induction of lung pathology. To interrogate whether reactivation of Mtb after CD4+ T cell depletion can be reversed, we employed interleukin (IL)-2/anti-IL-2 complex-mediated cell boost approaches. Although populations of non-CD4 lymphocytes, such as CD8+ memory T cells, natural killer (NK) cells and double-negative (DN) T cells significantly expanded after IL-2/anti-IL-2 complex treatment, progressive development of bacteremia and pathologic lung alterations could not be prevented. These data suggest that the failure to reverse Mtb reactivation is likely not due to anergy of the expanded cell subsets and rather indicates a limited potential for IL-2-complex-based therapies in the management of Mtb/HIV co-infection