The kinesin motor protein Kif7 is required for T-cell development and normal MHC expression on thymic epithelial cells (TEC) in the thymus

Abstract

Kif7 is a ciliary kinesin motor protein that regulates mammalian Hedgehog pathway activation through influencing structure of the primary cilium. Here we show that Kif7 is required for normal T-cell development, despite the fact that T-cells lack primary cilia. Analysis of Kif7-deficient thymus showed that Kif7-deficiency increases the early CD44+CD25+CD4-CD8- thymocyte progenitor population but reduces differentiation to CD4+CD8+ double positive (DP) cell. At the transition from DP to mature T-cell, Kif7-deficiency selectively delayed maturation to the CD8 lineage. Expression of CD5, which correlates with TCR signal strength, was reduced on DP and mature CD4 and CD8 cells, as a result of thymocyte-intrinsic Kif7-deficiency, and Kif7-deficient T-cells from radiation chimeras activated less efficiently when stimulated with anti-CD3 and anti-CD28 in vitro. Kif7-deficient thymocytes showed higher expression of the Hedgehog target gene Ptch1 than WT, but were less sensitive to treatment with recombinant Shh, and Kif7-deficient T-cell development was refractory to neutralisation of endogenous Hh proteins, indicating that Kif7-deficient thymocytes were unable to interpret changes in the Hedgehog signal. In addition, Kif7-deficiency reduced cell-surface MHCII expression on thymic epithelial cells.

In the fetal thymus, Gli3 in thymic epithelial cells promotes thymocyte positive selection and differentiation by repression ofShh

“…As expected, rHhip-treated WT FTOC had a higher proportion of SP4 and SP8 cells but a decreased percentage of DP cells than untreated controls ( Fig. 3 A,B) ( Lau et al, 2017 ). rHhip-treated Gli3 −/− FTOC had a significantly higher proportion of SP4 cells ( Fig.…”

Overexpression of kinesin superfamily members as prognostic biomarkers of breast cancer

“…Researches published demonstrated the correlation predicted by our bioinformatics analyses. KIF7 was reported to be required for T-cell development with the deficiency of KIF7 leading to the increase of premature CD44+CD25+CD4−CD8− thymocyte progenitor population while a decrease of differentiated CD4+CD8+ double-positive (DP) cell [89]. Furthermore, KIF20Aderived long peptides were identified bearing naturally processed epitopes recognized by CD4(+) T cells and CTLs, which induce tumor-specific T-helper type 1 (TH1) cells and CTLs in head-and-neck malignant tumor tissues [11].…”

Ciliary signalling in cancer

“…Defects in IFT-related proteins within immune cells may be expected and in some cases have been shown to impair immune cell maturation and function 47 . Loss of the ciliary protein Kif7 in immature thymocytes resulted in defects in Hh signaling, delayed their maturation to CD8+ cells, and impaired their interaction with the thymic epithelium in a manner that reduced MHCII expression on the surface of the epithelial cells 154 . These intriguing advances, coupled with the rich biology discussed earlier, make it likely that we are only at the dawn of understanding the complex role of ciliation in cancer.…”