title: A unique role for ITK in survival of invariant NKT cells associated with the p53-dependent pathway in mice.
abstract: Invariant NKT (iNKT) cells play important roles in the immune response. ITK and TXK/RLK are Tec family kinases that are expressed in iNKT cells; the expression level of ITK is ∼7-fold higher than that of TXK. Itk(-/-) mice have reduced iNKT cell frequency and numbers, with defects in development and cytokine secretion that are exacerbated in Itk/Txk double-knockout mice. In contrast, there is no iNKT cell defect in Txk(-/-) mice. To determine whether ITK and TXK play distinct roles in iNKT cell development and function, we examined mice that overexpress TXK in T cells at levels similar to Itk. Overexpression of TXK rescues the maturation and cytokine secretion of Itk(-/-) iNKT cells, as well as altered expression of transcription factors T-bet, eomesodermin, and PLZF. In contrast, the increased apoptosis observed in Itk(-/-) splenic iNKT cells is not affected by TXK overexpression, likely due to the lack of effect on the elevated expression of p53 regulated proapoptotic pathways Fas, Bax, and Bad in those cells. Supporting this idea, p53(-/-) and Bax(-/-) mice have increased splenic iNKT cells. Our results suggest that TXK plays an overlapping role with ITK in iNKT cell development and function but that ITK also has a unique function in the survival of iNKT cells, likely via a p53-dependent pathway.
authors.affiliation: Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16801, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qi
authors.forename: Weishan
authors.initials: W
authors.lastname: Huang
authors.forename: Yuting
authors.initials: Y
authors.lastname: Bai
authors.forename: Gabriel
authors.initials: G
authors.lastname: Balmus
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weiss
authors.forename: Avery
authors.initials: A
authors.lastname: August
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002470:Cell Survival / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005699:Galactosylceramides / Q000494:pharmacology; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D061251:Primary Cell Culture; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016207:Cytokines; D005699:Galactosylceramides; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C493154:alpha-galactosylceramide; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase