A TNF-p100 pathway subverts noncanonical NF-[kappa]B signaling in inflamed secondary lymphoid organs

Lymphotoxin-beta receptor (LT[beta]R) present on stromal cells engages the noncanonical NF-[kappa]B pathway to mediate RelB-dependent expressions of homeostatic chemokines, which direct steady-state ingress of naïve lymphocytes to secondary lymphoid organs (SLOs). In this pathway, NIK promotes partial proteolysis of p100 into p52 that induces nuclear translocation of the RelB NF-[kappa]B heterodimers. Microbial infections often deplete homeostatic chemokines; it is thought that infection-inflicted destruction of stromal cells results in the downregulation of these chemokines. Whether inflammation per se also regulates these processes remains unclear. We show that TNF accumulated upon non-infectious immunization of mice similarly downregulates the expressions of these chemokines and consequently diminishes the ingress of naïve lymphocytes in inflamed SLOs. Mechanistically, TNF inactivated NIK in LT[beta]R-stimulated cells and induced the synthesis of Nfkb2mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity as inhibitory I[kappa]B[delta]. Finally, a lack of p100 alleviated these TNF-mediated inhibitions in inflamed SLOs of immunized Nfkb2-/- mice. In sum, we reveal that an inhibitory TNF-p100 pathway modulates the adaptive compartment during immune responses. Synopsis Noncanonical NF-[kappa]B signaling produces homeostatic chemokines, which direct naïve lymphocytes into secondary lymphoid organs (SLOs). TNF accumulation in inflamed SLOs alters this homeostasis by subverting noncanonical signaling. LT[beta]R-stimulated noncanonical RelB NF-[kappa]B signaling produces homeostatic chemokines in SLOs. TNF abrogates LT[beta]R-stimulated noncanonical RelB activity. TNF inhibits NIK and induces the production inhibitory p100-I[kappa]B[delta]. A TNF-p100 pathway downregulates homeostatic chemokines in inflamed SLOs.