title: A mycolic acid-specific CD1-restricted T cell population contributes to acute and memory immune responses in human tuberculosis infection.
abstract: Current tuberculosis (TB) vaccine strategies are largely aimed at activating conventional T cell responses to mycobacterial protein antigens. However, the lipid-rich cell wall of Mycobacterium tuberculosis (M. tuberculosis) is essential for pathogenicity and provides targets for unconventional T cell recognition. Group 1 CD1-restricted T cells recognize mycobacterial lipids, but their function in human TB is unclear and their ability to establish memory is unknown. Here, we characterized T cells specific for mycolic acid (MA), the predominant mycobacterial cell wall lipid and key virulence factor, in patients with active TB infection. MA-specific T cells were predominant in TB patients at diagnosis, but were absent in uninfected bacillus Calmette-Guérin-vaccinated (BCG-vaccinated) controls. These T cells were CD1b restricted, detectable in blood and disease sites, produced both IFN-γ and IL-2, and exhibited effector and central memory phenotypes. MA-specific responses contracted markedly with declining pathogen burden and, in patients followed longitudinally, exhibited recall expansion upon antigen reencounter in vitro long after successful treatment, indicative of lipid-specific immunological memory. T cell recognition of MA is therefore a significant component of the acute adaptive and memory immune response in TB, suggesting that mycobacterial lipids may be promising targets for improved TB vaccines.
authors.affiliation: Tuberculosis Research Unit, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Montamat-Sicotte
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Millington
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Willcox
authors.forename: Suzie
authors.initials: S
authors.lastname: Hingley-Wilson
authors.forename: Sarah
authors.initials: S
authors.lastname: Hackforth
authors.forename: John
authors.initials: J
authors.lastname: Innes
authors.forename: Onn Min
authors.initials: OM
authors.lastname: Kon
authors.forename: David A
authors.initials: DA
authors.lastname: Lammas
authors.forename: David E
authors.initials: DE
authors.lastname: Minnikin
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Willcox
authors.forename: Ajit
authors.initials: A
authors.lastname: Lalvani
mesh_terms: D000208:Acute Disease; D056704:Adaptive Immunity; D000328:Adult; D000368:Aged; D000942:Antigens, Bacterial / Q000276:immunology*; D018949:Antigens, CD1 / Q000276:immunology*; D000995:Antitubercular Agents / Q000627:therapeutic use; D001500:BCG Vaccine / Q000276:immunology; D002473:Cell Wall / Q000276:immunology*; D002478:Cells, Cultured / Q000276:immunology; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D009171:Mycolic Acids / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control; D032581:Tuberculosis Vaccines; D014774:Virulence; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D018949:Antigens, CD1; D000995:Antitubercular Agents; D001500:BCG Vaccine; D007376:Interleukin-2; D009171:Mycolic Acids; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma