The Conventional Nature of Non-MHC-Restricted T Cells

Abstract

The definition "unconventional T cells" identifies T lymphocytes that recognize non-peptide antigens presented by monomorphic antigen-presenting molecules. Two cell populations recognize lipid antigens and small metabolites presented by CD1 and MR1 molecules, respectively. A third cell population expressing the TCR Vγ9Vδ2 is stimulated by small phosphorylated metabolites. In the recent past, we have learnt a lot about the selection, tissue distribution, gene transcription programs, mode of expansion after antigen recognition, and persistence of these cells. These studies depict their functions in immune homeostasis and diseases. Current investigations are revealing that unconventional T cells include distinct sub-populations, which display unexpected similarities to classical MHC-restricted T cells in terms of TCR repertoire diversity, antigen specificity variety, functional heterogeneity, and naïve-to-memory differentiation dynamic. This review discusses the latest findings with a particular emphasis on these T cells, which appear to be more conventional than previously appreciated, and with the perspective of using CD1 and MR1-restricted T cells in vaccination and immunotherapy.

Keywords: CD1; MR1; immunotherapy; lipid antigens; vaccines.

Figure 1

Modes of CD1-restricted TCR binding to CD1–lipid antigen complexes. (A) The TCR directly interacts with both the CD1 α1 and α2 domains and the bound lipid antigens. Key residues of the CDR3α and CDR3β loops directly contact the lipid antigens, allowing discrimination of small structural variations of their polar heads exposed to the solvent. (B) The TCR directly interacts with CD1 only and does not contact the lipid antigens. The antigens are often, but not always, headless lipids, which do not protrude out of the CD1 portals and probably induce small conformational changes favoring TCR binding. Lipid antigens that do not directly contact the TCR have been defined as “permissive.” (C) TCR binding is prevented by CD1 ligands that display large polar heads or contain solvent-exposed chemical groups that mediate repulsion with key residues of the TCR CDR3α and/or CDR3β loops. Ligands in this category have been defined as “non permissive.” (D) TCR binding occurs despite the presence of large and complex ligand polar heads, consisting of multiple sugar subunits. The TCR interacts with both CD1 and only a portion of the exposed lipid antigen head, which probably remains partially excluded from the binding surface area. This mode has not been supported by crystallographic studies, yet.

Figure 2

Heterogeneity of “adaptive like” CD1-restricted T cells. The sub-populations of CD1-restricted T cells reported so far as displaying close similarities to adaptive T cells are captured here in relation to their CD1 restriction, antigen sources, functions, and proposed immunological role. Invariant natural killer T cells have not been included because of their innate-like nature.

Figure 3

Functional diversity of MR1T cells. The heterogeneity of MR1T cells is illustrated in relation to the recognized antigen (yet unknown) and the functional phenotype of the clones isolated so far.