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NF-κB signaling mediates homeostatic maturation of new T cells

  1. Benedict Seddon2,3
  1. Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, NW7 1AA, United Kingdom

  1. Edited by Rafi Ahmed, Emory University, Atlanta, GA, and approved January 24, 2014 (received for review October 15, 2013)

Significance

Interleukin (IL)-7 is critical for the maintenance of the peripheral T-cell compartment of the adaptive immune system. Our study identifies a role for the Nuclear Factor κ-B (NF-κB) signalling pathway in the control of IL-7 receptor expression by T cells. Following thymic selection, new T cells specifically up-regulate IL-7R even as they leave the thymus, and we reveal that this expression is strictly NF-κB dependent. NF-κB signaling was only required transiently, however, and once fully mature, naive T cells did not require NF-κB signaling to maintain IL-7R expression. Therefore, we reveal a developmental role for NF-κB signaling for the normal maturation and function of new T cells.

Abstract

Interleukin (IL)-7 is critical for the maintenance of the peripheral T-cell compartment of the adaptive immune system. IL-7 receptor α ( IL-7Rα) expression is subject to developmental regulation and new T cells induce expression as they leave the thymus, which is essential for their long-term survival. It is not understood how this expression is regulated. Here, we identify a role for the Nuclear Factor κ-B (NF-κB) signaling pathway in controlling expression of IL-7Rα in new T cells. Perturbations to NF-κB signaling, either by deletion of Inhibitor of Kappa-B Kinase-2 (IKK2) or by inhibiting Rel dimer activity, prevented normal IL-7Rα expression in new T cells. Defective IL-7Rα expression resulted in impaired survival and homeostatic cell division responses by T cells that could be attributed to their failure to express IL-7Rα normally. Surprisingly, NF-κB signaling was only required transiently in new T cells to allow their normal expression of IL-7Rα, because IKK2 deletion in mature T cells had no effect on IL-7Rα expression or their normal homeostatic responsiveness. Therefore, we identify a developmental function for NF-κB signaling in the homeostatic maturation of new T cells, by regulating IL-7Rα expression.

Footnotes

  • ↵1Present address: Academic Department of Rheumatology, Center for Molecular and Cellular Biology of Inflammation, King’s College London, London SE1 1UL, United Kingdom.

  • ↵2To whom correspondence should be addressed. E-mail: benedict.seddon{at}ucl.ac.uk.

  • ↵3Present address: Institute of Immunity and Transplantation, Division of Infection and Immunity, University College of London, Royal Free Hospital, London NW3 2PF, United Kingdom.

  • Author contributions: A.S., S.C.L., and B.S. designed research; A.S. and G.C. performed research; A.S. and B.S. analyzed data; and A.S. and B.S. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1319397111/-/DCSupplemental.

Freely available online through the PNAS open access option.

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