NF-κB inducing kinase (NIK) is an essential post-transcriptional regulator of T-cell activation affecting F-actin dynamics and TCR signaling

J Autoimmun. 2018 Nov:94:110-121. doi: 10.1016/j.jaut.2018.07.017. Epub 2018 Jul 29.

Abstract

NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T cells using T-cell specific NIK-deficient (NIKΔT) mice. Despite showing normal development of lymphoid organs, NIKΔT mice were resistant to induction of CNS autoimmunity. T cells from NIKΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK-/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dynamics. In line with this we found that NIK-deficient T cells were hampered in phosphorylation of Zap70, LAT, AKT, ERK1/2 and PLCγ upon TCR engagement. Hence, our data disclose a hitherto unknown function of NIK in T-cell priming and differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / immunology*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Animals
  • Central Nervous System / immunology
  • Central Nervous System / pathology
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Activation*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / immunology
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / immunology
  • Myelin-Oligodendrocyte Glycoprotein / administration & dosage
  • NF-kappaB-Inducing Kinase
  • Peptide Fragments / administration & dosage
  • Phospholipase C gamma / genetics
  • Phospholipase C gamma / immunology
  • Phosphoproteins / genetics
  • Phosphoproteins / immunology
  • Primary Cell Culture
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction
  • Spleen / immunology
  • Spleen / pathology
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • T-bet Transcription Factor
  • ZAP-70 Protein-Tyrosine Kinase / genetics
  • ZAP-70 Protein-Tyrosine Kinase / immunology

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • Lat protein, mouse
  • Membrane Proteins
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Phosphoproteins
  • Receptors, Antigen, T-Cell
  • T-Box Domain Proteins
  • T-bet Transcription Factor
  • myelin oligodendrocyte glycoprotein (35-55)
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Phospholipase C gamma