c-Rel delivers a one-two punch in Th1 cell differentiation.

The differentiation of T helper cells into distinct functional subtypes is critical for mediating effective adaptive immune responses. The molecular mechanism by which a Th precursor cell (Thp) adopts a Th1 or Th2 phenotype involves a complex interplay between the induction of lineagespecific transcription factors, such as T-bet, Gata3, and c-Maf, and the stimulatory effects of the cytokine milieu, which are largely provided by antigenpresenting cells (APCs) (1). In the case of Th1 differentiation, antigen stimulation of a naive Thp causes simultaneous low-level expression of both the Th1-specific transcription factor T-bet and the Th2-specific factor Gata3, and coproduction of small amounts of IFN-γ and IL-4 (2, 3). Subsequent differentiation of Thp into Th1 cell is thought to occur via two other events, as shown in Figure 1. The first is upregulation of IL-12Rβ2 expression by T-bet, which amplifies the effects of IL-12 and strengthens signaling through STAT4 (3, 4). The second is activation of STAT1 via IFN-γ receptor engagement, which further upregulates T-bet expression in a positive feedback loop (4, 5). The net effects of T-bet, STAT4, and STAT1 activation then drive high-level production of IFN-γ by Th1 cells, which is necessary for antiviral immunity and other Th1-mediated immune functions. In addition to the effects of lineagespecific transcription factors, a number of more widely expressed factors have been shown to affect Th cell differentiation. In this issue of the JCI, Hilliard et al. report the effects of cRel deficiency on Th1-dependent immunity both in vitro and in vivo (6). c-Rel is a member of the family of NF-κB/Rel transcription factors, which includes four other mammalian members: RelA (p65), RelB, NF-κB1 (p50/p105), and NF-κB2 (p52/p100) (7). These five factors share a highly conserved Rel homology domain at their N-termini and play important roles in the development, activation, and homeostasis of the immune system. Studies of the NF-κB family members by targeted deletion of one or more family members in mice have so far shown differential effects on Th immune responses. Universal inhibition of all family members in transgenic mice overexpressing a proteaseresistant IκB results in an inability to mount a Th1 immune response (8). In contrast, mice deficient in the single factor NF-κB1 fail to optimally induce Gata3 and are resistant to allergic asthma, a Th2 cell–mediated disease (9). Our understanding of the role of NF-κB family members in Th differentiation is further complicated by COMMENTARY