Early innate responses to pathogens: pattern recognition by unconventional human T-cells

Abstract

Although typically viewed as a feature of innate immune responses, microbial pattern recognition is increasingly acknowledged as a function of particular cells nominally categorized within the adaptive immune system. Groundbreaking research over the past three years has shown how unconventional human T-cells carrying invariant or semi-invariant TCRs that are not restricted by classical MHC molecules sense microbial compounds via entirely novel antigen presenting pathways. This review will focus on the innate-like recognition of non-self metabolites by Vγ9/Vδ2 T-cells, mucosal-associated invariant T (MAIT) cells and germline-encoded mycolyl-reactive (GEM) T-cells, with an emphasis on early immune responses in acute infection.

Figure 1

Innate sensing of microbial pathogens by Toll-like receptors and unconventional T-cell receptors. Pattern recognition of clinically relevant microbial pathogens via TLR4 and TLR5, and TCRs expressed by Vγ9/Vδ2 T-cells, MAIT cells and GEM T-cells. Blue symbols, recognition; red symbols, no recognition.

Figure 2

Recognition of microbial metabolites by unconventional T-cells. (a) ‘Presentation’ of HMB-PP to the Vγ9/Vδ2 TCR in a BTN3-dependent manner: 1, Uptake of soluble HMB-PP released by extracellular bacteria, phagocytes or infected cells, via endocytosis and/or active/passive transport across the cell membrane (e.g. E. coli); 2, Transport of HMB-PP from endocytic vesicles across the membrane after phagocytosis or infection (e.g. Mycobacterium tuberculosis); 3, Release of HMB-PP into the cytosol by intracellular pathogens (e.g. Salmonella spp.); 4, Putative intracellular loading compartment for BTN3. High affinity ligand: HMB-PP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; low affinity ligand: IPP, isopentenyl pyrophosphate. Note that HMB-PP is a microbial metabolite, whereas IPP is present in all prokaryotic and eukaryotic cells. (b) Presentation of vitamin B2 metabolites to the MAIT TCR by MR1: 1, Uptake of soluble vitamin B2 metabolites released by extracellular bacteria, phagocytes or infected cells; 2, Shuttling of vitamin B2 metabolites to late endosomes; 3, Release of vitamin B2 metabolites into the cytosol; 4, MR1 loading compartment. High affinity ligand: 5-OP-RU, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil; low affinity ligand: RL-6,7-diMe, 6,7-dimethyl-8-d-ribityllumazine. APC, antigen-presenting cell; PMN, polymorphonuclear cell; IgV, immunoglobulin-like V ectodomain; IgC, immunoglobulin-like C ectodomain; LL, di-leucine motif; β2M, β₂-microglobulin; li, MHC class II-associated invariant chain (CD74).