title: Human invariant NKT cells are required for effective in vitro alloresponses.
abstract: NKT cells are a small subset of regulatory T cells conserved in humans and mice. In humans they express the Valpha24Jalpha18 invariant chain (hence invariant NKT (iNKT) cells) and are restricted by the glycolipid-presenting molecule CD1d. In mice, iNKT cells may enhance or inhibit anti-infectious and antitumor T cell responses but suppress autoimmune and alloreactive responses. We postulated that iNKT cells might also modulate human alloreactive responses. Using MLR assays we demonstrate that in the presence of the CD1d-presented glycolipid alpha-galactosylceramide (alphaGC) alloreactivity is enhanced (37 +/- 12%; p < 0.001) in an iNKT cell-dependent manner. iNKT cells are activated early during the course of the MLR, presumably by natural ligands. In MLR performed without exogenous ligands, depletion of iNKT cells significantly diminished the alloresponse in terms of proliferation (58.8 +/- 24%; p < 0.001) and IFN-gamma secretion (43.2 +/- 15.2%; p < 0.001). Importantly, adding back fresh iNKT cells restored the reactivity of iNKT cell-depleted MLR to near baseline levels. CD1d-blocking mAbs equally reduced the reactivity of the iNKT cell-replete and -depleted MLR compared with IgG control, indicating that the effect of iNKT cells in the in vitro alloresponse is CD1d-dependent. These findings suggest that human iNKT cells, although not essential for its development, can enhance the alloreactive response.
authors.affiliation: Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Scott
authors.initials: S
authors.lastname: Patterson
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kotsianidis
authors.forename: Antonio
authors.initials: A
authors.lastname: Almeida
authors.forename: Marianna
authors.initials: M
authors.lastname: Politou
authors.forename: Amin
authors.initials: A
authors.lastname: Rahemtulla
authors.forename: Bini
authors.initials: B
authors.lastname: Matthew
authors.forename: Richard R
authors.initials: RR
authors.lastname: Schmidt
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
authors.forename: Irene A G
authors.initials: IA
authors.lastname: Roberts
authors.forename: Anastasios
authors.initials: A
authors.lastname: Karadimitris
mesh_terms: D018949:Antigens, CD1 / Q000502:physiology; D055610:Antigens, CD1d; D017252:CD3 Complex / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000502:physiology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D017252:CD3 Complex; D005699:Galactosylceramides; D008024:Ligands; C493154:alpha-galactosylceramide