Dynamics of circulating lymphocytes responding to human experimental enterotoxigenic Escherichia coli infection

Abstract

Read more about EJI's first-time authors Enterotoxigenic Escherichia coli (ETEC) is an important cause of children's and travelers' diarrhea, with no licensed vaccine. This study aimed to explore the role of cellular immunity in protection against human ETEC infection. Nine volunteers were experimentally infected with ETEC, of which six developed diarrhea. Lymphocytes were collected from peripheral blood buffy coats, before and 3, 5, 6, 7, 10, and 28 days after dose ingestion, and 34 phenotypic and functional markers were examined by mass cytometry. Thirty-three cell populations, derived by manually merging 139 cell clusters from the X-shift unsupervised clustering algorithm, were analyzed. Initially, the diarrhea group responded with increased CD56dim CD16 + natural killer cells, dendritic cells tended to rise, and mucosalassociated invariant T cells decreased. On day 5-7, an increase in plasmablasts was paralleled by a consistent rise in CD4 + Th17-like effector memory and regulatory cell subsets. CD4 + Th17-like central memory cells peaked on day 10. All Th17-like cell populations showed increased expression of activation, gut-homing, and proliferation markers. Interestingly, in the nondiarrhea group, these same CD4 + Th17-like cell populations expanded earlier, normalizing around day 7. Earlier development of these CD4 + Th17-like cell populations in the nondiarrhea group may suggest a recall response and a potential role in controlling ETEC infections.

Conventional and unconventional T-cell responses contribute to the prediction of clinical outcome and causative bacterial pathogen in sepsis patients

“…In predicting 90-day mortality, increased expression of the activation marker CD25 on MAIT cells influenced survival prediction, in line with a recent description of highly activated MAIT cells in clinical and experimental sepsis [ 71 ]. The reduction in circulating Vδ2 + T cells and MAIT cells in patients with Gram-negative sepsis seen in the present study might reflect recruitment of these cells to sites of infection [ 72–74 ] and agrees with previous observations in septic patients [ 75–77 ] and volunteers challenged with Escherichia coli [ 78 ]. In contrast, our own previous analysis in a different sepsis cohort showed increased proportions of circulating Vγ9 + γδ T cells in patients infected with HMB-PP + pathogens [ 79 ], and others described higher levels of peripheral MAIT cells but not of γδ T cells in critically ill patients infected with Streptococcus spp.…”

Conventional and unconventional T cell responses contribute to the prediction of clinical outcome and causative bacterial pathogen in sepsis patients

“…In predicting 90 day mortality, increased expression of the activation marker CD25 on MAIT cells influenced survival prediction, in line with a recent description of highly activated MAIT cells in clinical and experimental sepsis [70]. The reduction in circulating Vδ2 + T cells and MAIT cells in patients with Gram-negative sepsis seen in the present study might reflect recruitment of these cells to sites of infection [71, 72, 73] and agrees with previous observations in septic patients [74, 75, 76] and volunteers challenged with E. coli [77]. In contrast, our own previous analysis in a different sepsis cohort showed increased proportions of circulating Vγ9 + γδ T cells in patients infected with HMB-PP + pathogens [78], and others described higher levels of peripheral MAIT cells but not of γδ T cells in critically ill patients infected with Streptococcus spp.…”

MAIT cell activation and recruitment in inflammation and tissue damage in acute appendicitis

“…The prevailing hypotheses potentially explaining the loss of circulating MAIT cells in infectious and inflammatory diseases include trafficking to and accumulation within infected and inflamed tissues, activation-induced cell death, and pyroptosis ( 37 – 43 , 45 , 47 , 61 , 63 – 69 ). However, MAIT cells were rapidly recovering in numbers in the blood of patients with APA following an appendectomy, and this supports that MAIT cells were only transiently sequestered out of circulation rather than irreversibly lost.…”

“…Circulating MAIT cells express high levels of gut-homing and inflammation-associated chemokine receptors, including CCR2, CCR5, CCR6, CCR9, and CXCR6 ( 14 , 27 – 30 ), as well as tissue-homing molecules including α4β1, α4β7, αΕβ7, and αLβ2 integrins ( 12 , 24 , 28 , 31 – 36 ). However, although MAIT cells are implicated in the setting of acute intestinal infections and inflammation, there is no conclusive evidence for their trafficking to the gut or mechanisms by which this may occur ( 2 , 37 – 47 ). In addition, many of these studies were conducted using circulating MAIT cell samples [reviewed in ( 2 )].…”