MAIT cells detect and efficiently lyse bacterially-infected epithelial cells.

Mucosal associated invariant T cells (MAIT) are innate T lymphocytes that detect a large variety of bacteria and yeasts. This recognition depends on the detection of microbial compounds presented by the evolutionarily conserved major-histocompatibility-complex (MHC) class I molecule, MR1. Here we show that MAIT cells display cytotoxic activity towards MR1 overexpressing non-hematopoietic cells cocultured with bacteria. The NK receptor, CD161, highly expressed by MAIT cells, modulated the cytokine but not the cytotoxic response triggered by bacteria infected cells. MAIT cells are also activated by and kill epithelial cells expressing endogenous levels of MRI after infection with the invasive bacteria Shigella flexneri. In contrast, MAIT cells were not activated by epithelial cells infected by Salmonella enterica Typhimurium. Finally, MAIT cells are activated in human volunteers receiving an attenuated strain of Shigella dysenteriae-1 tested as a potential vaccine. Thus, in humans, MAIT cells are the most abundant T cell subset able to detect and kill bacteria infected cells.

MR1B, a natural spliced isoform of the MHC-related 1 protein, is expressed as homodimers at the cell surface and activates MAIT cells.

The MHC-related 1 (MR1) protein is a monomorphic, evolutionarily conserved MHC class I-like molecule, which is necessary for the development and functions of mucosal-associated invariant T (MAIT) cells, a new subset of innate-like lymphocytes. Multiple isoforms of the MR1 gene are naturally transcribed, but only the full-length MR1A has been analyzed so far. Using transfected cell lines expressing an alternative spliced transcript, MR1B, characterized by the absence of the α3 extracellular domain, we show that MR1B is transcribed and glycosylated but remains in an immature (endoglycosidase H-sensitive) state. MR1B mostly accumulates in the ER, without interacting with proteins of the peptide-loading complex such as tapasin. Interestingly, it is nevertheless found expressed at the cell surface, independently of ß2-microglobulin, in a homodimeric form. MR1B is functional as its overexpression induces MAIT cell activation in vitro in the presence of bacteria. Altogether, these data show that MR1B displays several remarkable features, and probably plays a physiological role complementary to MR1A with respect to MAIT cell development and/or function.

B and T lymphocyte attenuator is highly expressed on CMV-specific T cells during infection and regulates their function.

B and T lymphocyte attenuator (BTLA), like its relative programmed cell death-1 (PD-1), is a receptor that negatively regulates murine T cell activation. However, its expression and function on human T cells is currently unknown. We report in this study on the expression of BTLA in human T cell subsets as well as its regulation on virus-specific T cells during primary human CMV infection. BTLA is expressed on human CD4(+) T cells during different stages of differentiation, whereas on CD8(+) T cells, it is found on naive T cells and is progressively downregulated in memory and differentiated effector-type cells. During primary CMV infection, BTLA was highly induced on CMV-specific CD8(+) T cells immediately following their differentiation from naive cells. After control of CMV infection, BTLA expression went down on memory CD8(+) cells. Engagement of BTLA by mAbs blocked CD3/CD28-mediated T cell proliferation and Th1 and Th2 cytokine secretion. Finally, in vitro blockade of the BTLA pathway augmented, as efficient as anti-PD-1 mAbs, allogeneic as well as CMV-specific CD8(+) T cell proliferation. Thus, our results suggest that, like PD-1, BTLA provides a potential target for enhancing the functional capacity of CTLs in viral infections.

PD-L2 is expressed on activated human T cells and regulates their function.

T-cell activation and proliferation are regulated by cosignaling adhesion molecules involved in positive or negative signals. Programmed death (PD)-1 is one of immune inhibitory molecules that is expressed in activated T cells and is a promising target for immunotherapy. Both PD-1 ligands, PD-L1 and PD-L2 are expressed on antigen presenting cells (APCs) involved in the dialogue between a T cell and an APC. Here, we analysed the expression of these ligands, especially for PD-L2, on T cells. PD-L2 appears to be expressed on activated CD4 and CD8T cell subsets. Moreover, as PD-1 molecule, PD-L2 engagement at the surface of T cells is able to down-modulate cytokine production and cell proliferation. These observations indicate that PD-L2 is expressed following activation and is involved in the regulation of T cell function, highlighting the level of complexity in the T cell cosignaling network.