Casting a wider net: Immunosurveillance by nonclassical MHC molecules

Abstract

Most studies of T lymphocytes focus on recognition of classical major histocompatibility complex (MHC) class I or II molecules presenting oligopeptides, yet there are numerous variations and exceptions of biological significance based on recognition of a wide variety of nonclassical MHC molecules. These include αβ and γδ T cells that recognize different class Ib molecules (CD1, MR-1, HLA-E, G, F, et al.) that are nearly monomorphic within a given species. Collectively, these T cells can be considered "unconventional," in part because they recognize lipids, metabolites, and modified peptides. Unlike classical MHC-specific cells, unconventional T cells generally exhibit limited T-cell antigen receptor (TCR) repertoires and often produce innate immune cell-like rapid effector responses. Exploiting this system in new generation vaccines for human immunodeficiency virus (HIV), tuberculosis (TB), other infectious agents, and cancer was the focus of a recent workshop, "Immune Surveillance by Non-classical MHC Molecules: Improving Diversity for Antigens," sponsored by the National Institute of Allergy and Infectious Diseases. Here, we summarize salient points presented regarding the basic immunobiology of unconventional T cells, recent advances in methodologies to measure unconventional T-cell activity in diseases, and approaches to harness their considerable clinical potential.

Fig 1. Overview of the crystal structure of the HLA-F–antigen complex.

Ribbon diagrams of the extracellular portion of HLA-F in complex with β2m. The α1, α2, and α3 domains of HLA-F are in magenta. CDRs are part of the variable chains of T-cell receptors shown in cyan, where these molecules bind to their specific antigen, shown in yellow. The T-cell receptor complex with TCR-α and TCR-β chains is shown in gray. Figure provided by Dr. Erin Adams. αβ T cells, alpha beta T cells; CD1, (involved in the presentation of lipid antigens to T cells); CDR, Complementarity-determining region; γδ T cells, gamma delta T cells; HLA, human leukocyte antigen; MAIT, Mucosal associated invariant T; MHC, Major Histocompatibility Complex; MR1, major histocompatibility complex, class I-related protein; TCR, T-cell antigen receptor.

Fig 2. The MHC fold has evolved to present repertoires of chemically diverse antigens.

Representative structures of the platform domains of classical MHC presentation of peptide antigens (H2-Kb with DEV8 peptide, PDB ID: 2CKB, on left [67]); CD1 presentation of lipid antigens (CD1d with α-Galactosylceramide, PDB ID: 1ZT4, in middle [68]); and MR1 presentation of small molecule metabolites (MR1 with 5-OP-RU, which forms a Schiff base with MR1 residue Lys43, PDB ID, on right). Figure provided by Drs. Erin Adams and Sidonia Eckle. 5-OP-RU, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil.