Human NKT cells express granulysin and exhibit antimycobacterial activity.
Human NKT cells are a unique subset of T cells that express an invariant V alpha 24 TCR that recognizes the nonclassical Ag-presenting molecule CD1d. Activation of NKT cells is greatly augmented by the marine sponge-derived glycolipid alpha-galactosylceramide (alpha GalCer). Because human monocyte-derived cells express CD1d and can harbor the intracellular pathogen Mycobacterium tuberculosis, we asked whether the addition of alpha GalCer could be used to induce effector functions of NKT cells against infected monocytes, macrophages, and monocyte-derived dendritic cells. NKT cells secreted IFN-gamma, proliferated, and exerted lytic activity in response to alpha GalCer-pulsed monocyte-derived cells. Importantly, alpha GalCer-activated NKT cells restricted the growth of intracellular M. tuberculosis in a CD1d-dependent manner. NKT cells that exhibited antimycobacterial activity also expressed granulysin, an antimicrobial peptide shown to mediate an antimycobacterial activity through perturbation of the mycobacterial surface. Degranulation of NKT cells resulted in depletion of granulysin and abrogation of antimycobacterial activity. The detection of CD1d in granulomas of tuberculosis patients supports the potential interaction of NKT cells with CD1d-expressing cells at the site of disease activity. These studies provide evidence that alpha Gal Cer-activated CD1d-restricted T cells can participate in human host defense against M. tuberculosis infection.
Gansert
Jennifer L
JL
Division of Hematology and Oncology and Department of Microbiology and Immunology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095, USA.
Kiessler
Viviane
V
Engele
Matthias
M
Wittke
Frederick
F
Röllinghoff
Martin
M
Krensky
Alan M
AM
Porcelli
Steven A
SA
Modlin
Robert L
RL
Stenger
Steffen
S
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000276:immunology; D017951:Antigen Presentation; D018949:Antigens, CD1 / Q000096:biosynthesis; D055610:Antigens, CD1d; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis*; D002999:Clone Cells; D003594:Cytoplasmic Granules / Q000276:immunology / Q000382:microbiology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005699:Galactosylceramides / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000276:immunology*; D011161:Porifera; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control
D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D018949:Antigens, CD1; D055610:Antigens, CD1d; D000945:Antigens, Differentiation, T-Lymphocyte; C526877:CD1D protein, human; C075005:GNLY protein, human; D005699:Galactosylceramides