Mucosal associated invariant T (MAIT) cells in Vibrio cholerae infection and vaccination

Background

Cholera is an acute dehydrating diarrheal illness caused by Vibrio cholerae infection, accounting for more than 3 million cases and 100,000 deaths a year globally. In endemic countries, young children bear a large burden of disease.

Knowledge gap

Despite this, currently available cholera vaccines achieve a lower efficacy and shorter duration of protection in young children than in adults for reasons that are poorly understood, while such differences in protection are not evident following natural infection. We have recently shown, in a cohort of Bangladeshi children, that younger children given oral cholera vaccine mount lower V. cholerae polysaccharide-specific antibody responses compared to older children and adults.

Relevance

Mucosal-associated invariant T (MAIT) cells are recently described innate-like T cells, representing 1-10% of circulating T cells, and found in abundance in the intestinal mucosa, mesenteric lymph nodes, and liver. MAIT cells are predominantly CD8+ and restricted by the non-polymorphic MHC-related protein 1 (MR1), and activated by pathogen-derived vitamin B metabolites. Despite their innate-like features, recent studies have found that MAIT cells have surprising heterogeneity in their TCR repertoire and can discriminate between pathogen-derived ligands in a clonotype-dependent manner.

In collaboration with scientists at the University of Utah, we have examined both peripheral and duodenal MAIT cells in humans with severe cholera. We found that MAIT cells are activated in both the peripheral and mucosal compartments during cholera infection, and that they are associated with higher class-switched V. cholerae polysaccharide-specific antibody responses. Additionally, in a set of in vitro studies using primary MAIT cells and MAIT clones expanded from healthy individuals, we have shown that MAIT cells promote B cell differentiation and antibody production. We have also used transcriptomic analysis to demonstrate that activated MAIT cells have increased expression of CD40L and APRIL, factors known to play a role in B cell activation. Thus, we hypothesize that in mucosal infection and vaccination, MAIT cells play an important role in bridging innate and adaptive immune responses, including a possible effect on polysaccharide-specific responses.

Building on these data, and taking advantage of our longstanding collaboration with scientists at the University of Utah and Harvard Medical School, we propose to use V. cholerae as a prototypical human enteric pathogen to understand the adaptive capacity and B cell impact of MAIT cells during enteric infection and vaccination.

Hypothesis

We will test the hypothesis that a subset of MAIT cells, when activated following infection or vaccination, undergo clonal expansion and provide help to B cells through MR1-dependent and -independent interactions to enhance polysaccharide-specific antibody production.

Objectives

The objective of this study is:

• To characterize clonal expansions of MAIT cells during human cholera infection and vaccination;
• To determine the mechanisms through which MAIT cells affect B cell maturation.

Methods

Isolation of PBMCs from blood by density gradient centrifugation from younger and older children vaccinees and infected younger children and clonal expansion of single sorted MAIT cells.

Outcome measures/variables

Generation of clones from the vaccinees and infected persons with Cholera.

Currently available cholera vaccines achieve a lower efficacy and shorter duration of protection in young children than in adults for reasons that are poorly understood, while such differences in protection are not evident following natural infection. We have recently shown, in a cohort of Bangladeshi children, that younger children given oral cholera vaccine mount lower V. cholerae polysaccharide-specific antibody responses compared to older children and adults.

The objective of this study is:

• To characterize clonal expansions of MAIT cells during human cholera infection and vaccination;
• To determine the mechanisms through which MAIT cells affect B cell maturation.

Generation of MAIT cell clones from the vaccinees and infected persons with cholera may help to understand and use those as therapeutics for control of cholera.