Combined Deficiency of p50 and cRel in CD4+ T Cells Reveals an Essential Requirement for Nuclear Factor κB in Regulating Mature T Cell Survival and In Vivo Function

Abstract

Signaling pathways involved in regulating T cell proliferation and survival are not well understood. Here we have investigated a possible role of the nuclear factor (NF)-κB pathway in regulating mature T cell function by using CD4+ T cells from p50−/− cRel−/− mice, which exhibit virtually no inducible κB site binding activity. Studies with these mice indicate an essential role of T cell receptor (TCR)-induced NF-κB in regulating interleukin (IL)-2 expression, cell cycle entry, and survival of T cells. Our results further indicate that NF-κB regulates TCR-induced expression of antiapoptotic Bcl-2 family members. Strikingly, retroviral transduction of CD4+ T cells with the NF-κB–inducing IκB kinase β showed that NF-κB activation is not only necessary but also sufficient for T cell survival. In contrast, our results indicate a lack of involvement of NF-κB in both IL-2 and Akt-induced survival pathways. In vivo, p50−/− cRel−/− mice showed impaired superantigen-induced T cell responses as well as decreased numbers of effector/memory and regulatory CD4+ T cells. These findings provide the first demonstration of a role for NF-κB proteins in regulating T cell function in vivo and establish a critically important function of NF-κB in TCR-induced regulation of survival.

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

“…This leads to NF-kB activation and consequent cell survival via induction of antiapoptotic genes, and to proliferation via synthesis of IL-2 and GM-CSF. Studies with wild-type and p50 À/À c-Rel À/À CD4 þ T cells demonstrated that activation of NF-kB following TCR engagement in conjunction with CD28 costimulation is critically required to induce expression of antiapoptotic genes bcl-xl and bcl-2 and promote Tcell viability (Zheng et al, 2003). Similar results were observed in CD4 þ T cells expressing a super-repressor form of IkBa (Khoshnan et al, 2000).…”

Crosstalk via the NF-κB signaling system

“…In addition, B-cells derived from nfkb1 -/-, rela -/-tnfr1 -/-or crel -/-mice exhibited proliferation defects in vitro (Alcamo et al, 2002;Kontgen et al, 1995;Sha et al, 1995). Similar studies have also established an important role for canonical NF-κB dimers in thymocyte maturation (Boothby et al, 1997), T-cell proliferation, survival and in vivo function (Zheng et al, 2003), and in dendritic cell development (Ouaaz et al, 2002). In sum, these genetic analyses have established a role for the canonical NF-κB pathway in innate and adaptive immune compartments, in both cell activation and development.…”

c‐Rel: A pioneer in directing regulatory T‐cell lineage commitment?

“…A previous study has shown that mice deficient in both c-Rel and NF-kB1/p50 have reduced numbers of splenic CD4 1 CD25 1 T cells [23], suggesting that either c-Rel or NF-kB1 or both, are required for Treg development. Deenick et al [17], Visekruna et al [18] and others have now analyzed mice lacking each member of the NF-kB proteins known to mediate TCR/CD28 signals and observed that c-Rel-deficient mice have reduced numbers of Foxp3 1 CD4SP cells in the thymus and in the periphery [17][18][19]21].…”