CD1d-restricted T cell activation by nonlipidic small molecules.
In addition to NK T cells expressing invariant Valpha14 or Valpha24 T cell receptors (TCRs), the CD1d-restricted T cell repertoire is comprised of T cells with diverse TCRs that mediate inflammation during autoimmune and infectious disease. Here we describe the isolation of human Valpha24(-) T cells that are activated by antigen and CD1d. Mass spectrometric and NMR studies revealed that the stimulatory compounds were neither peptidic nor lipidic but instead were composed of sulfur and aromatic hydrocarbon rings, corresponding to the general structure of phenyl pentamethyldihydrobenzofuran sulfonates. Studies of the molecular mechanism of T cell activation showed that a clonotypic Valpha2/Vbeta21 TCR transmitted activating signals, which were highly specific for hydroxylation and methylation patterns at the terminal structures of stimulatory compounds. These studies provide evidence for noninvariant CD1d-restricted T cells in humans and identify the complete molecular structure of a nonlipidic small molecule that activates T cells through an alphabeta TCR.
Van Rhijn
Ildiko
I
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, 1 Jimmy Fund Way, Boston, MA 02115, USA.
Young
David C
DC
Im
Jin Seon
JS
Levery
Steven B
SB
Illarionov
Petr A
PA
Besra
Gurdyal S
GS
Porcelli
Steven A
SA
Gumperz
Jenny
J
Cheng
Tan-Yun
TY
Moody
D Branch
DB
D018949:Antigens, CD1 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D055610:Antigens, CD1d; D001190:Arylsulfonates / Q000737:chemistry* / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
D018949:Antigens, CD1; D055610:Antigens, CD1d; D001190:Arylsulfonates; D001572:Benzofurans; C526877:CD1D protein, human; D016693:Receptors, Antigen, T-Cell, alpha-beta; C492586:phenyl 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonate