The Role of IKK Signalling in T cells

The Inhibitor of Kappa B Kinase (IKK) complex is a key component of canonical NF-κB signalling. More recently, the IKK complex has emerged as a regulator of extrinsic cell death pathways by directly limiting the activity of RIPK1. Normal thymocyte development is solely reliant on repression of TNF triggered cell death by the IKK complex, independently of NF-κB activation. However, the role of IKK signalling in T cells after activation remains unclear. To address this, we analysed activation of IKK2 deficient TCR transgenic T cells. While early activation events were normal, proliferation of T cell blasts was impaired. Cell cycle progression in IKK2 deficient T cells was also unperturbed. Instead, dividing cells were more sensitive to extrinsic apoptosis since inhibition of RIPK1 kinase activity almost completely rescued cell survival. Consequently, anti-viral IKK2 deficient T cell responses were profoundly diminished in vivo. Transcriptomic analysis of activated IKK2 deficient T cells revealed defective expression of Tnfaip3, that encodes A20, a negative regulator of NF-κB. We examined whether A20 induction was required to protect IKK2 deficient T cells from death. Inhibition of IKK activity in A20 deficient T cells in vitro uncovered a role for A20 in regulating cell death. Mice with combined A20 and IKK2 deficiency exhibited defective CD8+ SP thymocyte development and substantial peripheral T cell lymphopenia. However, this phenotype was almost completely reversed by inhibition of RIPK1 kinase activity and partially rescued upon deletion of TNFR1 in vivo. Since receptors additional to TNFR1 appeared to be triggering naïve T cell death, we subsequently identified roles for IKK and A20 in regulation of the Fas apoptotic pathway. Together, our data reveals that IKK signalling protects T cells from RIPK1 dependent death in both an NF-κB dependent and independent manner, and downstream of multiple receptors