Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for nuclear factor kappaB in regulating mature T cell survival and in vivo function.
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)-kappaB pathway in regulating mature T cell function by using CD4+ T cells from p50-/- cRel-/- mice, which exhibit virtually no inducible kappaB site binding activity. Studies with these mice indicate an essential role of T cell receptor (TCR)-induced NF-kappaB in regulating interleukin (IL)-2 expression, cell cycle entry, and survival of T cells. Our results further indicate that NF-kappaB regulates TCR-induced expression of antiapoptotic Bcl-2 family members. Strikingly, retroviral transduction of CD4+ T cells with the NF-kappaB-inducing IkappaB kinase beta showed that NF-kappaB activation is not only necessary but also sufficient for T cell survival. In contrast, our results indicate a lack of involvement of NF-kappaB 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-kappaB proteins in regulating T cell function in vivo and establish a critically important function of NF-kappaB in TCR-induced regulation of survival.
Zheng
Ye
Y
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Vig
Monika
M
Lyons
Jesse
J
Van Parijs
Luk
L
Beg
Amer A
AA
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002453:Cell Cycle; D016923:Cell Death; D002470:Cell Survival; D051550:I-kappa B Kinase; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis
D018106:CD28 Antigens; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse