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Abstract
NKT cells are a distinct subset that have developmental requirements that often differ from conventional T cells. Here, we show that NKT-specific deletion of Hdac3 results in a severe reduction in the number of iNKT cells, particularly of NKT1 cells. In addition, there is decreased cytokine production by Hdac3-deficient NKT2 and NKT17 cells. Hdac3-deficient iNKT cells have increased cell death that is not rescued by transgenic expression of Bcl-2 or Bcl-xL. Hdac3-deficient iNKT cells have less Cyto-ID staining and lower LC3A/B expression, indicative of reduced autophagy. Interestingly, Hdac3-deficient iNKT cells also have lower expression of the nutrient receptors GLUT1, CD71 and CD98, which would increase the need for autophagy when nutrients are limiting. Therefore, Hdac3 is required for iNKT cell development and differentiation.
Highlights
Invariant Natural Killer T cells are an innate lineage of T cells characterized by the expression of an invariant Vα14-Jα18 TCR-α chain that pairs with limited TCRβ–chains Vβ7, or Vβ8 or Vβ2 in mice[1, 2]
NKT2 cells develop in Stage 1 and Stage 2, NKT17 cell are found in Stage 2, whereas NKT1 cells are in Stage 3
Using PLZF-cre Histone deacetylases (Hdacs)[3] cKO mice, we demonstrate loss of Hdac[3] leads to a decreased autophagy and a severe defect in Invariant Natural Killer T (iNKT) cell numbers, of NKT1 effector cells
Summary
Invariant Natural Killer T (iNKT) cells are an innate lineage of T cells characterized by the expression of an invariant Vα14-Jα18 TCR-α chain that pairs with limited TCRβ–chains Vβ7, or Vβ8 or Vβ2 in mice[1, 2]. Loss of Egr[2] in T cells leads to a block in iNKT cell development with increased cell death, supporting the importance of Bcl-2 in iNKT cell survival as well[13]. Requirement for autophagy in iNKT cells was cell intrinsic and not due to impaired CD1d-dependent-lipid antigen presentation to developing thymocytes, supporting the critical and unique role of autophagy in iNKT cell biology[21,22,23]. Hdac[3] is required for positive selection of conventional αβ T cells and iNKT cells in the thymus[29,30,31]. The transcriptional regulator Hdac[3] plays a critical role in regulation of iNKT cell survival and effector function during development
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