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Review
. 2019 Feb 21;15(2):e1007567.
doi: 10.1371/journal.ppat.1007567. eCollection 2019 Feb.

Casting a wider net: Immunosurveillance by nonclassical MHC molecules

M Patricia D'Souza  1 , Erin Adams  2 , John D Altman  3 , Michael E Birnbaum  4 , Cesar Boggiano  1 , Giulia Casorati  5 , Yueh-Hsiu Chien  6 , Anthony Conley  1 , Sidonia Barbara Guiomar Eckle  7 , Klaus Früh  8 , Timothy Gondré-Lewis  9 , Namir Hassan  10 , Huang Huang  6 , Lakshmi Jayashankar  11 , Anne G Kasmar  12 , Nina Kunwar  1 , Judith Lavelle  13 , David M Lewinsohn  8 , Branch Moody  14 , Louis Picker  8 , Lakshmi Ramachandra  9 , Nilabh Shastri  15 , Peter Parham  6 , Andrew J McMichael  16 , Jonathan W Yewdell  17
Affiliations
Review

Casting a wider net: Immunosurveillance by nonclassical MHC molecules

M Patricia D'Souza et al. PLoS Pathog. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
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
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.
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