Cytotoxic lymphocyte death drives monocyte activation and TNF/IFN-γ synergism in TBK1 deficiency

Abstract TBK1 deficiency drives the pathogenesis of inborn errors of cell death (IECDs). However, the underlying cellular mechanisms remain unclear. Here, we identified a novel homozygous loss-of-function TBK1 variant resulting in exon 18 deletion (p.R621Sfs*21) that led to loss of TBK1 expression in a patient with systemic juvenile idiopathic arthritis (sJIA). The patient’s myeloid cells exhibited predominantly upregulated inflammatory responses, including TNF, NF-κB, and IFN (interferon)-γ signaling, while type I IFN responses were partially impaired in responses to agonists of pattern recognition receptors (PRRs). Analysis of the patient’s peripheral blood mononuclear cells (PBMCs) and healthy donor-derived TBK1 -knockout T cells showed that TBK1 -deficient cytotoxic lymphocytes are more susceptible to RIPK1-dependent cell death. Cell-cell communication analysis and combined treatment targeting TNF and IFN-γ highlighted a driving role of TNF/IFN-γ synergism in inflammatory activation of monocytes/T cells in the patient’s PBMCs, which was triggered by uncontrolled programmed cell death resulting from TBK1 deficiency. Long-term follow-up demonstrated that combined TNF and JAK inhibitor therapy was effective in suppressing the patient’s inflammatory responses. Our results identified a novel pathogenic TBK1 variant and demonstrated that cytotoxic lymphocytes are the primary drivers of aberrant cell death through a T cell-myeloid axis dependent on TNF/IFN-γ synergism. These results support combined TNF and JAK inhibition as an effective therapeutic strategy for TBK1 deficiency.