Abstract
The hemolytic uremic syndrome associated with diarrhea, a consequence of Shiga toxin (Stx)-producing Escherichia coli infection, is a common cause of pediatric acute renal failure in Argentina. Stx type 2a (Stx2a) causes direct damage to renal cells and induces local inflammatory responses that involve secretion of inflammatory mediators and the recruitment of innate immune cells. γδ T cells constitute a subset of T lymphocytes, which act as early sensors of cellular stress and infection. They can exert cytotoxicity against infected and transformed cells, and produce cytokines and chemokines. In this study, we investigated the activation of human peripheral γδ T cells in response to the incubation with Stx2a-stimulated human glomerular endothelial cells (HGEC) or their conditioned medium, by analyzing in γδ T lymphocytes, the expression of CD69, CD107a, and perforin, and the production of TNF-α and IFN-γ. In addition, we evaluated by confocal microscopy the contact between γδ T cells and HGEC. This analysis showed an augmentation in cellular interactions in the presence of Stx2a-stimulated HGEC compared to untreated HGEC. Furthermore, we observed an increase in cytokine production and CD107a expression, together with a decrease in intracellular perforin when γδ T cells were incubated with Stx2a-treated HGEC or their conditioned medium. Interestingly, the blocking of TNF-α by Etanercept reversed the changes in the parameters measured in γδ T cells incubated with Stx2a-treated HGEC supernatants. Altogether, our results suggest that soluble factors released by Stx2a-stimulated HGEC modulate the activation of γδ T cells, being TNF-α a key player during this process.
Highlights
Hemolytic uremic syndrome (HUS) is a late acute onset of symptoms that can appear after an initial intestinal infection with Shiga Toxin (Stx)-producing Escherichia coli (STEC)
Under our experimental conditions, we did not detect a modulation by Stx type 2a (Stx2a) of the level of the activation marker CD69 on gd T cells (Figure 1D), suggesting that gd T lymphocytes’ responses differ when cultured with Stx2astimulated human glomerular endothelial cells (HGEC), compared to IFN-g and TNF-a secretion
There are not previous publications reporting the role of gd T cells during the pathogenesis of HUS, since most of them have studied their role in cattle, calves (Menge et al, 2004), and mice (Obata et al, 2015)
Summary
Hemolytic uremic syndrome (HUS) is a late acute onset of symptoms that can appear after an initial intestinal infection with Shiga Toxin (Stx)-producing Escherichia coli (STEC). STEC strains expressing Stx are the most common etiologic pathogen responsible for severe cases of HUS in Argentina, and the subtype Stx2a causes more serious illnesses than strains encoding Stx2c (Fitzgerald et al, 2019). Toxin A-fragments appear to re-fold into their active conformation (Hazes and Read, 1997) All this process results in host cell protein synthesis inhibition, activation of the ribotoxic and endoplasmic reticulum stress responses, and in the induction of apoptosis (of epithelial, endothelial, lymphoid and myeloid cells), autophagy and increased expression of pro-inflammatory cytokines and chemokines (Johannes and Römer, 2010), which contribute to tissue damage in the colon and the development of HUS and central nervous system complications. They can exert the non-secretory mechanism of cytotoxicity by the interaction between Fas and FasL
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