Rel/NF-kappaB family member RelA regulates NK1.1- to NK1.1+ transition as well as IL-15-induced expansion of NKT cells.
Development of NKT cells was shown to depend on lymphotoxin (LT) and IL-15 signaling pathways as well as on cytokine receptor common gamma chain. After positive selection, NKT-cell precursors transit through progressive maturation stages including proliferative expansion within the NK1.1(-) window. The transcription factors that integrate different signaling pathways into different stages of NKT-cell development are not well characterized. Here, we show that the Rel/NF-kappaB family member RelA regulates the NK1.1(-) to NK1.1(+) transition during NKT-cell development. RelA is also required for both IL-15- and IL-7-induced proliferation of CD44(hi)NK1.1(-) NKT-cell precursors. Activation of the invariant NKT-cell receptor induces both IL-15 receptor alpha and gamma chains' expression in an NF-kappaB-dependent manner, suggesting a molecular mechanism by which NF-kappaB regulates NKT-cell development. NF-kappaB also regulates TCR-induced expression of LT-alpha and LT-beta within NKT cells. In contrast to previous reports, however, we show that LT signaling is dispensable for thymic NKT-cell development but is essential for their colonization of peripheral organs such as liver.
Vallabhapurapu
Sivakumar
S
Leibniz-Institute for Age Research, Fritz-Lipmann-Institute, Jena, Germany.
Powolny-Budnicka
Iwona
I
Riemann
Marc
M
Schmid
Roland M
RM
Paxian
Stephan
S
Pfeffer
Klaus
K
Körner
Heinrich
H
Weih
Falk
F
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018960:Hyaluronan Receptors / Q000276:immunology; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology*; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism; D015851:Interleukin-7 / Q000494:pharmacology; D008025:Ligases / Q000145:classification / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000145:classification / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
D018960:Hyaluronan Receptors; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D015851:Interleukin-7; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases