TY - JOUR
T1 - A subset of CD8α/β+ invariant NKT cells in a humanized mouse model
AU - Wen, Xiangshu
AU - Kim, Seil
AU - Xiong, Ran
AU - Li, Michelle
AU - Lawrenczyk, Agnieszka
AU - Huang, Xue
AU - Chen, Si Yi
AU - Rao, Ping
AU - Besra, Gurdyal S.
AU - Dellabona, Paolo
AU - Casorati, Giulia
AU - Porcelli, Steven A.
AU - Akbari, Omid
AU - Exley, Mark A.
AU - Yuan, Weiming
N1 - Publisher Copyright:
Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2015/8/15
Y1 - 2015/8/15
N2 - Invariant NKT (iNKT) cells are unconventional innate-like T cells demonstrating potent antitumor function in conventional mouse models. However, the iNKT cell ligands have had limited efficacy in human antitumor clinical trials, mostly due to the profound differences in the properties and compositions of iNKT cells between the two species, including the presence of a CD8+ subset of iNKT cells only in humans. To build reliable in vivo models for studying human iNKT cells, we recently developed the first humanized mouse model (hCD1d-KI) with human CD1d knocked in. To further humanize the mouse model, we now introduced the human invariant NKT TCRa-chain (Va24Ja18) into the hCD1d-knockin mice. Similar to humans, this humanized mouse model developed a subset of CD8α/β+ iNKT cells among other human-like iNKT subsets. The presence of the CD8α/β+ iNKT cells in the thymus suggests that these cells developed in the thymus. In the periphery, these NKT cells showed a strong Th1-biased cytokine response and potent cytotoxicity for syngeneic tumor cells upon activation, as do human CD8α/β+ iNKT cells. The low binding avidity of iNKT TCRs to the human CD1d/lipid complex and high prevalence of Vb7 TCRb among the CD8+ iNKT cells strongly point to a low avidity-based developmental program for these iNKT cells, which included the suppression of Th-POK and upregulation of eomesodermin transcriptional factors. Our establishment of this extensively humanized mouse model phenotypically and functionally reflecting the human CD1d/iNKT TCR system will greatly facilitate the future design and optimization of iNKT cell-based immunotherapies.
AB - Invariant NKT (iNKT) cells are unconventional innate-like T cells demonstrating potent antitumor function in conventional mouse models. However, the iNKT cell ligands have had limited efficacy in human antitumor clinical trials, mostly due to the profound differences in the properties and compositions of iNKT cells between the two species, including the presence of a CD8+ subset of iNKT cells only in humans. To build reliable in vivo models for studying human iNKT cells, we recently developed the first humanized mouse model (hCD1d-KI) with human CD1d knocked in. To further humanize the mouse model, we now introduced the human invariant NKT TCRa-chain (Va24Ja18) into the hCD1d-knockin mice. Similar to humans, this humanized mouse model developed a subset of CD8α/β+ iNKT cells among other human-like iNKT subsets. The presence of the CD8α/β+ iNKT cells in the thymus suggests that these cells developed in the thymus. In the periphery, these NKT cells showed a strong Th1-biased cytokine response and potent cytotoxicity for syngeneic tumor cells upon activation, as do human CD8α/β+ iNKT cells. The low binding avidity of iNKT TCRs to the human CD1d/lipid complex and high prevalence of Vb7 TCRb among the CD8+ iNKT cells strongly point to a low avidity-based developmental program for these iNKT cells, which included the suppression of Th-POK and upregulation of eomesodermin transcriptional factors. Our establishment of this extensively humanized mouse model phenotypically and functionally reflecting the human CD1d/iNKT TCR system will greatly facilitate the future design and optimization of iNKT cell-based immunotherapies.
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U2 - 10.4049/jimmunol.1500574
DO - 10.4049/jimmunol.1500574
M3 - Article
C2 - 26157173
AN - SCOPUS:84938917935
SN - 0022-1767
VL - 195
SP - 1459
EP - 1469
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -