Differential requirement for Rel/nuclear factor κB 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)-kappaB family of transcription factors were required in both hematopoietic and nonhematopoietic cells for normal development of thymic NKT cells. Activation of NF-kappaB via the classical IkappaBalpha-regulated pathway was required in a cell autonomous manner for the transition of NK-1.1-negative precursors that express the TCR Valpha14-Jalpha18 chain to mature NK-1.1-positive NKT cells. The Rel/NF-kappaB 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-kappaB-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-kappaB family members in hematopoietic and nonhematopoietic cells regulate NKT cell development with a unique requirement for NIK-mediated activation of RelB in thymic stroma.