Chronic helminth infections induce T-cell hyporesponsiveness, which may affect immune responses to other pathogens or to vaccines. This study investigates the influence of Treg activity on proliferation and cytokine responses to BCG and Plasmodium falciparum-parasitized RBC in Indonesian schoolchildren. Geohelminth-infected children's in vitro T-cell proliferation to either BCG or pRBC was reduced compared to that of uninfected children. Although the frequency of CD41 T cells was similar regardless of infection status, the suppressive activity differed between geohelminth-infected and geohelminthuninfected groups: Ag-specific proliferative responses increased upon CD4 1 CD25 hi T-cell depletion in geohelminth-infected subjects only. In addition, IFN-c production in response to both BCG and parasitized RBC was increased after removal of CD4These data demonstrate that geohelminth-associated Treg influence immune responses to bystander Ag of mycobacteria and plasmodia. Geohelminth-induced immune modulation may have important consequences for co-endemic infections and vaccine trials.
To study the effect of repeated challenge of the innate immune system with pathogen-associated molecular patterns, cytokine responses to schistosomal lipids and bacterial lipopolysaccharide (LPS) were analyzed in schoolchildren living in an area in Gabon where schistosomiasis, a helminth infection that is chronic in nature, is endemic. A schistosomal phosphatidylserine (PS) fraction containing the Toll-like receptor (TLR)-2 ligand lyso-PS stimulated the production of interleukin (IL)-8, IL-10, IL-6, and tumor necrosis factor (TNF)-alpha in children without Schistosoma haematobium infection. However, in infected children, the responses to this stimulus were lower, in particular for production of IL-8 and TNF-alpha. Responses to the TLR4 ligand, LPS, followed a similar pattern. In contrast, schistosomal adult worm glycolipids that did not stimulate any of the TLRs tested induced IL-8 and IL-6 responses that were significantly higher in schistosome-infected children than in schistosome-uninfected children. These results indicate that relentless exposure to pathogens can lead to altered responses to TLR ligands.
SummaryMycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine has been associated with beneficial effects on overall childhood mortality in lowincome countries; this cannot be explained merely by the prevention of tuberculosis (TB) deaths. The beneficial effects of BCG vaccine could be the result of either strengthening of pro-inflammatory mechanisms, helping neonates to fight infections, or the induction of an immune-regulatory network restricting overt inflammation and intense pathology. We aimed to study the effect of live BCG on the ability of dendritic cells (DCs) to polarize T-cell responses. Monocyte-derived DCs were matured in the presence or absence of BCG. The DC phenotype was assessed by CD83 expression, interleukin-12 (IL-12) and IL-10 production, as well as for the ability to polarize T-cell responses. Following stimulation with CD40 ligand, DCs matured in the presence of BCG showed enhanced IL-10 and diminished IL-12 production. These DCs primed naive T cells to develop into IL-10-producing T cells, with no T helper 1 or T helper 2 bias. These results suggest that BCG vaccination might result in the development of IL-10-producing DCs as well as IL-10-producing T cells that could contribute to restricting overt inflammation in infants exposed to pathogens and thus lead to lower infant mortality.
SummaryBeta cells presenting islet epitopes are recognized and destroyed by autoreactive CD8 T cells in type 1 diabetes. These islet-specific T cells are believed to react with epitopes binding with high affinity to human leucocyte antigen (HLA) expressed on beta cells. However, this assumption might be flawed in case of islet autoimmunity. We evaluated T cell recognition of the complete array of preproinsulin (PPI) peptides with regard to HLA binding affinity and T cell recognition. In a comprehensive approach, 203 overlapping 9-10mer PPI peptides were tested for HLA-A2 binding and subjected to binding algorithms. Subsequently, a high-throughput assay was employed to detect PPI-specific T cells in patient blood, in which conditional HLA ligands were destabilized by ultraviolet irradiation and HLA molecules refolded with arrays of PPI peptides, followed by quantum-dot labelling and T cell staining. Analysis of patient blood revealed high frequencies of CD8 T cells recognizing very low HLA binding peptides. Of 28 peptides binding to HLA-A2, a majority was predicted not to bind. Unpredicted peptides bound mainly with low affinities. HLA binding affinity and immunogenicity may not correlate in autoimmunity. Algorithms used to predict high-affinity HLA peptide binders discount the majority of low-affinity HLA binding epitopes. Appreciation that peptides binding HLA with very low affinity can act as targets of autoreactive T cells may help to understand loss of tolerance and disease pathogenesis and possibly point to tissue-specific immune intervention targets.
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