A Cell-Intrinsic Requirement for NF-κB–Inducing Kinase in CD4 and CD8 T Cell Memory

Abstract

NF-κB-inducing kinase (NIK, MAP3K14) is an essential kinase linking a subset of TNF receptor family members to the noncanonical NF-κB pathway. In order to assess the cell-intrinsic role of NIK in murine T cell function, we generated mixed bone marrow chimeras using bone marrow from NIK knockout (NIK KO) and wild type (WT) donor mice and infected the chimeras with lymphocytic choriomeningitis virus (LCMV). The chimeras possess an apparently normal immune system including a mixture of NIK KO and WT T cells, and the virus was cleared normally. Comparison of the NIK KO and WT CD4 and CD8 T cell responses at 8 days post-infection revealed modest but significant differences in the acute response. In both CD4 and CD8 compartments, there were relatively fewer activated (CD44hi) NIK KO T cells, but within the CD44hi population, a comparable percentage of the activated cells produced IFN-γ in response to ex vivo stimulation with antigenic LCMV peptides, although IL-7R expression was reduced in the NIK KO CD8 T cells. Assessment of the LCMV-specific memory at 65 days postinfection revealed many more LCMV-specific WT memory T cells than NIK KO memory T cells in both the CD4 and CD8 compartments, although the small number of surviving NIK KO memory T cells responded to secondary challenge with virus. These results demonstrate a cell-intrinsic requirement for NIK in the generation and/or maintenance of memory T cells in response to acute viral infection.

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

“…Several reports have previously linked different members of the canonical and noncanonical NFκB pathway with T-cell memory (12,13,47). Our results confirmed this role and show how NFκB signaling regulates the generation of memory T cells in the context of infection.…”

“…One of these is NFκB. NFκB signaling has been previously implicated in the maintenance of naïve T cells and generation of memory T cells (12,13), although the molecular mechanisms regarding how NFκB regulates these processes remain undefined. NFκB signaling is coupled to the TCR through PKCθ (14).…”

T Cell–Intrinsic Function of the Noncanonical NF-κB Pathway in the Regulation of GM-CSF Expression and Experimental Autoimmune Encephalomyelitis Pathogenesis

“…Nevertheless, emerging evidence suggests a role for this pathway in the regulation of T-cell functions (10–12). In particular, recent work from others and us reveals that mice deficient in NIK are refractory to the induction of a T cell-dependent autoimmunity, experimental autoimmune encephalomyelitis (EAE) (10, 13).…”

TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4⁺ T-Lymphocytes

“…NIK is also important for generation and maintenance of CD4 + and CD8 + memory T cells in response to LCMV infection (Rowe et al 2013). 4-1BB signaling activates the noncanonical NF-κB pathway through the cIAP1-dependent degradation of TRAF3 in CD8 + T cells .…”