Differential requirement for Rel/nuclear factor kappa B family members in natural killer T cell development.
Natural killer T (NKT) cells have been implicated in diverse immune responses ranging from suppression of autoimmunity to tumor rejection. Thymus-dependent NKT cells are positively selected by the major histocompatibility complex class I-like molecule CD1d, but the molecular events downstream of CD1d are still poorly understood. Here, we show that distinct members of the Rel/nuclear factor (NF)-kappa B family of transcription factors were required in both hematopoietic and nonhematopoietic cells for normal development of thymic NKT cells. Activation of NF-kappa B via the classical I kappa B alpha-regulated pathway was required in a cell autonomous manner for the transition of NK-1.1-negative precursors that express the TCR V alpha 14-J alpha 18 chain to mature NK-1.1-positive NKT cells. The Rel/NF-kappa B family member RelB, on the other hand, had to be expressed in radiation resistant thymic stromal cells for the generation of early NK-1.1-negative NKT precursors. Moreover, NF-kappa B-inducing kinase (NIK) was required for both constitutive thymic DNA binding of RelB and the specific induction of RelB complexes in vitro. Thus, distinct Rel/NF-kappa B family members in hematopoietic and nonhematopoietic cells regulate NKT cell development with a unique requirement for NIK-mediated activation of RelB in thymic stroma.
Sivakumar
Vallabhapurapu
V
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, 76021 Karlsruhe, Germany.
Hammond
Kirsten J L
KJ
Howells
Norma
N
Pfeffer
Klaus
K
Weih
Falk
F
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D053259:Lymphotoxin beta Receptor; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D019409:Interleukin-15; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D020569:Proto-Oncogene Proteins c-rel; D018124:Receptors, Tumor Necrosis Factor; D000097782:NF-kappaB-Inducing Kinase; C505699:Ltbr protein, mouse