Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)β clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRβ clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes. Our results demonstrate that host exposure to antigen may drive clonal expansion of MAIT cells with increased functional avidity, suggesting a role for specific vaccination strategies to increase the frequency and potency of MAIT cells to optimize effector function.

A rare human allele renders MR1 unable to present microbially derived antigen, resulting in a selective loss of MAIT cells.

Significance: Alongside αβ T cells and B cells, γδ T cells comprise a major component of the adaptive immune system, although a lack of bona fide ligands has hindered understanding of their function. γδ T cells are key mediators of epithelial immune surveillance and have a purported capacity for employing diverse ligand engagement mechanisms beyond the dogmas of conventional αβ T cell–human leukocyte antigen restriction. Here, we found blood- and gut-resident Vδ1/2⁻γδ T cells bound to MR1 tetramers in a metabolite-independent mechanism distinct from mucosal-associated invariant T cells and provide insight into a unique antibody-like MR1 recognition mode. This reshapes our understanding of the ligand recognition principles of γδ T cells and how they differ from αβ T cells.

Malaria drives the adaptive differentiation of the human γδ T cell repertoire.

MR1-restricted MAIT cells recognize vitamin B metabolites, which are generated by a broad range of bacteria, from Escherichia coli to Mycobacterium tuberculosis and BCG. MAIT cells have been described as innate sensors of infection as they accumulate early in infected tissues. MAIT cells maintain an activated phenotype throughout the course of infections, secrete inflammatory cytokines and have the potential to directly kill infected cells, playing an important role in shaping the host response. In this review, we will discuss the current knowledge regarding the molecular mechanisms that underline MAIT cells activation in sterile and non-sterile inflammatory conditions.

Tryptophan degradation is an immune escape strategy shared by many tumors. However, cancer cells' compensatory mechanisms remain unclear. We demonstrate here that a shortage of tryptophan caused by expression of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) resulted in ATF4-dependent upregulation of several amino acid transporters, including SLC1A5 and its truncated isoforms, which in turn enhanced tryptophan and glutamine uptake. Importantly, SLC1A5 failed to be upregulated in resting human T cells kept under low tryptophan conditions but was enhanced upon cognate antigen T-cell receptor engagement. Our results highlight key differences in the ability of tumor and T cells to adapt to tryptophan starvation and provide important insights into the poor prognosis of tumors coexpressing IDO and SLC1A5. Cancer Res; 76(21); 6193–204. ©2016 AACR.