Contrasting roles for IKK regulated inflammatory signalling pathways for development and maintenance of type 1 and adaptive 𝛄δ T cells

The inhibitor of kappa B kinase complex (IKK) is a critical regulator of cell death and inflammatory signaling in multiple cell types. Phosphorylation of IκB proteins by IKK results in their degradation and consequent activation of NF-κB transcription factors. RIPK1, a critical cell death regulator, is also a direct target of IKK kinase activity, thereby repressing its cell death activity. In αβ T cells, the RIPK1 kinase activity of IKK is critical for normal thymic development while mature αβ T cells require IKK for both activation of NF-κB dependent survival programmes, and repression of RIPK1. γδ T cells play a unique and versatile role in host immunity with specific effector functions that enables them to act as early responders in immune defence. The role of IKK regulated pathways in their development and survival is not known. Here, we use mouse genetics to dissect the function of IKK and downstream pathways in the normal homeostasis of γδ T cells. We find that IKK expression is critical to establish a replete γδ T cell compartment, but that requires vary between different subsets. Type 1 γδ T cells require IKK dependent NF-κB activation for their generation, while IKK is redundant for development of adaptive γδ T cells. Instead, IKK dependent NF-κB activation is required for their longterm survival. We also find evidence that IKK repression of RIPK1 is required for survival of peripheral but not thymic γδ T cells. Ablation of CASPASE8 did not rescue γδ T cells in the absence of IKK but rather revealed a potent sensitivity of all γδ subsets to necroptosis, that was rescued by kinase dead RIPK1. Overall, we reveal critical requirements for IKK regulated inflammatory pathways by γδ T cells that contrast with those of αβ T cells, and between different subsets, highlighting the complexity of the regulation of these pathways in the adaptive immune system.