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Abstract
Invariant Natural Killer T (iNKT) cells are a unique subset of T lymphocytes that have been implicated in both promoting and suppressing a multitude of immune responses. In mice, iNKT cells express T cell antigen receptors (TCRs) comprising a unique TCRα rearrangement between the Trav11 and Traj18 gene segments. When paired with certain Trbv TCRβ chains, these TCRs recognize lipid antigens presented by the major histocompatibility complex (MHC) class I-like molecule, CD1d. Until recently, the sole model of iNKT deficiency targeted the Jα18, which is absolutely required to form the TCR with the appropriate antigenic specificity. However, these mice were demonstrated to have a large reduction in TCR repertoire diversity, which could confound results arising from studies using these mice. Here, we have created a new NKT-deficient mouse strain using transcription activator-like effector nuclease (TALEN) technology to only disrupt the expression of Jα18, leaving the remaining Jα repertoire unperturbed. We confirm that these mice lack iNKT cells and do not respond to lipid antigen stimulation while the development of conventional T cells, regulatory T cells, and type Ib NKT cells is normal. This new mouse strain will serve as a new model of iNKT cell deficiency to facilitate our understanding of iNKT biology.
Highlights
The majority of αβTCR+ T cells recognize peptide antigens presented by conventional polymorphic major histocompatibility complex (MHC) I or MHC II molecules, a fraction of T cells deviates from this rule
Most studies of these cells focus on type I, or Invariant Natural Killer T (iNKT) cells, which are the most prevalent natural killer T (NKT) cells in mice3. iNKT cells express a T cell antigen receptors (TCRs) that is the product of a canonical rearrangement between the Trav[11] (Vα14) gene segment (Trav[10] or Vα24 in human) and the Traj[18] (Jα18) gene segment, with a CDR3αregion invariant at the amino acid level[4,5]
Because the amino acids coded by the Jα1 8 segments in the final TCRαchain of the iNKT TCR are absolutely essential to the recognition of CD1d24, no iNKT cells develop in absence of Jα18, as no other Jαgene segment appears to be able to compensate[11]
Summary
The majority of αβTCR+ T cells recognize peptide antigens presented by conventional polymorphic MHC I or MHC II molecules, a fraction of T cells deviates from this rule. INKT cells express a TCR that is the product of a canonical rearrangement between the Trav[11] (Vα14) gene segment (Trav[10] or Vα24 in human) and the Traj[18] (Jα18) gene segment, with a CDR3αregion invariant at the amino acid level[4,5]. This Vα14 invariant chain is co-expressed with a limited set of Vβchains, predominantly Trbv[] (Vβ8.2), Trbv[29] (Vβ7) and Trbv[1] (Vβ2) in mice and Trbv[] (Vβ11) in humans. Because most type II NKT cells do not use the Jα1 8 gene segment as part of their TCRs, this population is expected to still be intact in Jα18 deficient mice
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