NF-κB signaling mediates homeostatic maturation of new T cells

Abstract

Interleukin (IL)-7 is critical for the maintenance of the peripheral T-cell compartment of the adaptive immune system. IL-7 receptor α ( IL-7Rα) expression is subject to developmental regulation and new T cells induce expression as they leave the thymus, which is essential for their long-term survival. It is not understood how this expression is regulated. Here, we identify a role for the Nuclear Factor κ-B (NF-κB) signaling pathway in controlling expression of IL-7Rα in new T cells. Perturbations to NF-κB signaling, either by deletion of Inhibitor of Kappa-B Kinase-2 (IKK2) or by inhibiting Rel dimer activity, prevented normal IL-7Rα expression in new T cells. Defective IL-7Rα expression resulted in impaired survival and homeostatic cell division responses by T cells that could be attributed to their failure to express IL-7Rα normally. Surprisingly, NF-κB signaling was only required transiently in new T cells to allow their normal expression of IL-7Rα, because IKK2 deletion in mature T cells had no effect on IL-7Rα expression or their normal homeostatic responsiveness. Therefore, we identify a developmental function for NF-κB signaling in the homeostatic maturation of new T cells, by regulating IL-7Rα expression. M aintaining T lymphocytes in sufficient numbers and at an appropriate composition of differentiation states and subtypes is essential for effective immunity. The immune system has evolved a number of homeostatic mechanisms to ensure the size and composition of the T-cell compartment remains remarkably stable over time. The cytokine interleukin (IL)-7 plays a central role in regulating homeostasis of the T-cell compartment. It is essential for normal development of αβ and γδ T cells in the thymus and provides vital survival signals for both naive and memory T cells in the periphery (1). IL-7 is produced by stromal cell components in bone marrow, thymus, and in peripheral lymphoid compartments (2), and there is extensive evidence that production of IL-7 is a key factor that determines and limits the overall size of the peripheral T-cell compartment (3, 4). The receptor for IL-7 is a member of the common-gamma chain (γc) family of cytokine receptors and consists of a heterodimeric complex of IL-7Rα and γc (5).In T cells, IL-7 signaling is primarily regulated at the level of IL-7Rα expression. During T-cell development in the thymus, expression of IL-7Rα by thymocytes is subject to dynamic developmental regulation. IL-7Rα is essential for survival and development of CD4 CD8 double negative (DN) thymocytes (6). Expression is lost at the CD4 CD8 double positive (DP) stage, ensuring that onward development of DP thymocytes is restricted to those that successfully undergo positive selection (7). Immediately following selection, however, IL-7Rα is immediately reexpressed and recent studies suggest that the strength of T-cell receptor (TCR)-mediated positive selection signaling determines the extent of reexpression by SP thymocytes (8). Following egress from the thymus, new T cells continue to mature as recent ...

Basal NF-κB controls IL-7 responsiveness of quiescent naïve T cells

“…In contrast, our findings suggest that NF-κB-dependent survival of naïve T cells relies, at least in part, on Bcl-2 upregulation on IL-7 exposure. Supporting our results, Silva et al (33) recently reported that IKKβ is required for IL-7Rα expression and homeostatic proliferation. Together with our findings, both studies define a role for NF-κB in the control of naïve T cells homeostasis in both lymphoreplete and lymphopenic hosts.…”

“…As in mice, de novo IL-7Rα reexpression in human T cells was impaired by pharmacological inhibition of NF-κB following exposure to IL-7. By contrast, deletion of IKKβ in mouse postthymic T cells did not affect constitutive levels of IL-7Rα (33), suggesting that in mature T cells NF-κB may be required for de novo IL-7Rα reexpression but not for its physiological maintenance. TNF stimulation has been reported to up-regulate IL7R mRNA in human HeLa cells in an NF-κB-dependent manner (43), and chromatin immunoprecipitation and sequencing data from the ENCODE project revealed RelA binding to the homologous IL7R ECR2 sequence in human lymphoblastoid cell lines (44).…”

Zap70 Is Essential for Long-Term Survival of Naive CD8 T Cells

“…The number of peripheral F5 T cells in such chimeras represents the equilibrium between thymic generation of new F5 T cells and loss of peripheral mature T cells in the presence of low Zap70 expression level. Recent thymic emigrants (RTE) in F5 mice can be readily identified by expression profile of HSA hi CD45RB lo Qa2 lo (31). In F5 TetZap70 chimeras fed dox, a higher proportion of F5 T cells expressed HSA, and this population was reduced when mice were taken off Dox for 7 days (Fig.…”

“…During their maturation, RTE express lower IL-7Rα than mature T cells (32) and this contributes to reduced survival and LIP by RTE (31). In F5 mice, F5 T cells upregulate IL-7Rα expression following egress from the thymus therefore for a time, RTE in F5 mice express low levels of IL-7Rα compared with mature naive F5 T cells (31). High levels of IL-7 in vivo can promote T cell survival in the absence of Zap70 expression (Fig.…”

“…Analysing competition between control and F5 TetZap70 T cells, that express lower levels of Zap70 as they leave the thymus, identified the RTE stage as a specific bottle neck for the generation of mature peripheral F5 TetZap70 T cells in competitive chimeras. F5 TetZap70 T cells were almost completely absent from the periphery of mixed chimeras, and the few T cells present were HSA hi IL-7Rɑ lo RTE (31). F5 TetZap70 T cells are capable of developing into fully mature peripheral F5 T cells since T cells with a mature HSA lo IL-7R hi phenotype are evident in F5 TetZap70 mice (24).…”