Editors' ChoiceImmunology

TNF drives thymocyte development

Sci. Signal.  02 Aug 2016:
Vol. 9, Issue 439, pp. ec176
DOI: 10.1126/scisignal.aah6738

Canonical activation of the transcription factor nuclear factor κB (NF-κB) requires phosphorylation of the inhibitor of κB (IκB) protein by the IκB kinases (IKK1 and IKK2), which results in degradation of IκB, releasing the NF-κB dimers to translocate to the nucleus. The development of thymocytes (T cell precursors) in the thymus requires NF-κB activity at various stages, which is thought to depend on signals from the T cell receptor (TCR). However, the multiprotein CBM complex through which the TCR normally activates NF-κB is not required for thymocyte development, suggesting that the TCR activates NF-κB in another way or that another receptor activates NF-κB. Webb et al. generated mice lacking IKK1 and IKK2 specifically in T cells and found that the earliest stages of thymocyte development were unaffected. However, the development of CD4 or CD8 single-positive (SP) thymocytes from double-positive (DP) cells was blocked. IKK1/2-deficient SP thymocytes were more sensitive than their wild-type counterparts to tumor necrosis factor (TNF)–induced apoptosis in vitro. Blocking TNF signaling with a neutralizing antibody or knocking out TNF receptor 1 (TNFR1) prevented IKK1/2-deficient SP thymocytes from undergoing apoptosis in vivo. The expression of particular NF-κB target genes, such as those encoding the inhibitor of apoptosis proteins (IAPs), protects many cell types from TNF-induced apoptosis. RNA sequencing analysis showed the TNF-induced expression of these genes was reduced in IKK1/2-deficient thymocytes. Together, these data suggest that NF-κB activation by TNF is required for the survival and development of SP thymocytes in the thymus.

L. V. Webb, S. C. Ley, B. Seddon, TNF activation of NF-κB is essential for development of single-positive thymocytes. J. Exp. Med. 213, 1399–1407 (2016). [PubMed]