IKK2/NFkB signaling controls lung resident CD8 T cell memory during influenza infection

CD8 tissue resident memory (TRM) cells are especially suited to control pathogen spread at mucosal sites. However, their maintenance in lung is limited. Here, we found that enhancing NFkB signaling in T cells once memory to influenza is established increased pro-survival Bcl-2 and CD122 levels boosting lung CD8 TRM maintenance. By contrast, enhancing NFkB signals during the contraction phase of the response led to a defect in TRM differentiation without impairing recirculating memory subsets. Specifically, inducible activation of NFkB via constitutive active IKK2 or tumor necrosis factor (TNF) interfered with tumor growth factor beta (TGF{beta}) signaling resulting in defects of lung CD8 TRM imprinting molecules CD69, CD103, Runx3 and Eomes. Conversely, inhibiting NFkB signals not only recovered but improved the transcriptional signature and generation of lung CD8 TRM. Thus, NFkB signaling is a critical regulator of tissue resident memory, whose levels can be tuned at specific times during infection to boost lung CD8 TRM.