Date Published: February 21, 2019
Publisher: Public Library of Science
Author(s): M. Patricia D’Souza, Erin Adams, John D. Altman, Michael E. Birnbaum, Cesar Boggiano, Giulia Casorati, Yueh-hsiu Chien, Anthony Conley, Sidonia Barbara Guiomar Eckle, Klaus Früh, Timothy Gondré-Lewis, Namir Hassan, Huang Huang, Lakshmi Jayashankar, Anne G. Kasmar, Nina Kunwar, Judith Lavelle, David M. Lewinsohn, Branch Moody, Louis Picker, Lakshmi Ramachandra, Nilabh Shastri, Peter Parham, Andrew J. McMichael, Jonathan W. Yewdell, Tom C. Hobman.
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.
Tuberculosis (TB)  and HIV  infection kill more than 2.6 million individuals per year worldwide (refer to Table 1 for acronyms and abbreviations). Devising novel approaches to elicit effective immunity is essential to global public health, because traditional vaccine approaches have failed to prevent infection or control either disease. Experts generally agree that effective vaccines for these diseases may need to harness the remarkable abilities of T cells to detect and clear intracellular pathogens, particularly T cells that recognize nonclassical MHC molecules.
Humans express 18 nonclassical MHC class I and class II molecules. Despite widely disparate amino acid sequences, all family members exhibit a broadly similar structure, with a ligand binding groove at the distal end of the molecule that typically presents a small molecule (oligopeptide, lipid, or metabolite) for interaction with an immune cell receptor (see Fig 2). Nonclassical class II molecules, HLA-DM and HLA-DO, are non-peptide binding class II MHC-II homologs, that function to edit the peptides presented by MHC class II molecules. They are not known to directly recognize T cells or other immune cells. Nonclassical class I molecules include 5 encoded by MHC genes (HLA-E, F, G, MICA, and MICAB which are MHC I chain-related protein A and protein B and 11 encoded by non-MHC genes (ULBP, are a family of human cell-surface molecules distantly related to classic MHC I molecules, MR1, CD1a-e, HFE, is a protein that is similar to MHC I-type proteins and associates with beta 2-microglobulin and regulates iron absorption, FcRn, is the neonatal Fc receptor, ZAG, is zinc-α2-glycoprotein and EPCR is endothelial Protein C Receptor). All but HFE, FcRn, and ZAG are known to interact with either T cells or NK cells. All but EPCR, ZAG, ULBP, MIC A, and MIC B form heterodimers with β2-microgloubulin (β2m) to achieve their native structure. Eight nonclassical MHC class I molecules are currently viewed as promising targets for HIV or TB vaccines—HLA-E, HLA-F, CD1a-e, and MR1.
Understanding and manipulating nonconventional T cells requires identifying the activating ligands bound to class Ib molecules and delineating the TCR repertoire elicited. In many cases, this requires the development of novel technologies.
Due largely to the history of discoveries in cellular immunology, primacy has been traditionally given to the study of classical class I molecules. Pioneers of nonclassical MHC molecule research vividly recount having to overcome skepticism that class Ib molecules are important—in part because of the circular argument that they were not widely studied.