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

Casting a wider net: Immunosurveillance by nonclassical MHC molecules.

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Division of AIDS, NIAID, Bethesda, Maryland, United States of America.
University of Chicago, Chicago, Illinois, United States of America.
Emory University, Atlanta, Georgia, United States of America.
Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
San Raffaele Scientific Institute, Milano, Italy.
Stanford University, Stanford, California, United States of America.
Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
Oregon Health & Science University, Portland, Oregon, United States of America.
Division of Allergy, Immunology and Transplantation, NIAID, Bethesda, Maryland, United States of America.
Immunocore Limited, Abingdon, United Kingdom.
Columbus Technologies, Contractor to NIAID, Bethesda, Maryland, United States of America.
Bill & Melinda Gates Foundation, Seattle, Washington, United States of America.
Officer of the Director, NIAID, Bethesda, Maryland, United States of America.
Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
University of California, Berkeley, California, United States of America.
University of Oxford, Oxford, United Kingdom.
Laboratory of Viral Diseases, NIAID, Bethesda, Maryland, United States of America.


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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The authors have declared that no competing interests exist.

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