Lineage relationships and differentiation of natural killer (NK) T cells: intrathymic selection and interleukin (IL)-4 production in the absence of NKR-P1 and Ly49 molecules.
In this report, we have assessed the lineage relationships and cytokine dependency of natural killer (NK) T cells compared with mainstream TCR-alphabeta T cells and NK cells. For this purpose, we studied common gamma chain (gamma c)-deficient mice, which demonstrate a selective defect in CD3- NK cell development relative to conventional TCR-alphabeta T cells. NK thymocytes differentiate in gamma c- mice as shown by the normal percentage of TCR Vbeta8+ CD4-CD8- cells and the normal quantity of thymic Va14-Jalpha281 mRNA that characterize the NK T repertoire. However, gamma c-deficient NK thymocytes fail to coexpress the NK-associated markers NKR-P1 or Ly49, yet retain characteristic expression of the cytokine receptors interleukin (IL)-7R alpha and IL-2Rbeta. Despite these phenotypic abnormalities, gamma c- NK thymocytes could produce normal amounts of IL-4. These results define a maturational progression of NK thymocyte differentiation where intrathymic selection and IL-4-producing capacity can be clearly dissociated from the acquisition of the NK phenotype. Moreover, these data suggest a closer ontogenic relationship of NK T cells to TCR-alphabeta T cells than to NK cells with respect to cytokine dependency. We also failed to detect peripheral NK T cells in these mice, demonstrating that gamma c-dependent interactions are required for export and/or survival of NK T cells from the thymus. These results suggest a stepwise pattern of differentiation for thymically derived NK T cells: primary selection via their invariant TCR to confer the IL-4-producing phenotype, followed by acquisition of NK-associated markers and maturation/export to the periphery.
Lantz
O
O
Institut National de la Santé et de la Recherche Medicale U267, Hôpital Paul Brousse, Villejuif, France.
Sharara
L I
LI
Tilloy
F
F
Andersson
A
A
DiSanto
J P
JP
D000818:Animals; D000950:Antigens, Ly; D000954:Antigens, Surface / Q000502:physiology*; D002454:Cell Differentiation; D005434:Flow Cytometry; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D055651:NK Cell Lectin-Like Receptor Subfamily B; D055630:Receptors, NK Cell Lectin-Like; D016176:T-Lymphocyte Subsets / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology*
D000950:Antigens, Ly; D000954:Antigens, Surface; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D055630:Receptors, NK Cell Lectin-Like; D015847:Interleukin-4