TY - JOUR
T1 - Inducible down-regulation of MHC class I results in natural killer cell tolerance
AU - Bern, Michael D.
AU - Parikh, Bijal A.
AU - Yang, Liping
AU - Beckman, Diana L.
AU - Poursine‑Laurent, Jennifer
AU - Yokoyama, Wayne M.
N1 - Funding Information:
This work was supported by National Institutes of Health grants R01AI129545 and R01AI131680 (to W.M. Yokoyama) and F30DK112466 (to M.D. Bern). The authors declare no competing financial interests.
Funding Information:
We thank J. Michael White (Transgenic, Knockout, and Micro-Injection Core at Washington University) for blastocyst injections of B2mtm1a ES cells and Andrea Lin for technical assistance. This work was supported by National Institutes of Health grants R01AI129545 and R01AI131680 (to W.M. Yokoyama) and F30DK112466 (to M.D. Bern).
Publisher Copyright:
© 2018 Bern et al.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Natural killer (NK) cells are innate lymphocytes that are thought to kill cells that down-regulate MHC class I (MHC-I) through “missing-self” recognition. NK cells from B2m −/− mice that lack surface MHC-I, however, are not autoreactive as predicted by the missing-self hypothesis. As a result, it is unclear if MHC-I down-regulation in vivo induces NK cell reactivity or tolerance to missing-self. Here, we generated a floxed B2m mouse to acutely down-regulate MHC-I in vivo in a host that normally expresses MHC-I. Global down-regulation of MHC-I induced NK cell hyporesponsiveness and tolerance to missing-self without overt missing-self reactivity. In contrast, down-regulation of MHC-I on a small fraction of hematopoietic cells triggered missing-self reactivity. Surprisingly, down-regulation of MHC-I only on CD4 + T cells predominately induced tolerance to missing-self without resetting NK cell responsiveness. In this setting, inflammation triggered substantial missing-self reactivity. These results show that MHC-I down-regulation can induce either NK cell tolerance or killing in vivo and that inflammation promotes missing-self reactivity.
AB - Natural killer (NK) cells are innate lymphocytes that are thought to kill cells that down-regulate MHC class I (MHC-I) through “missing-self” recognition. NK cells from B2m −/− mice that lack surface MHC-I, however, are not autoreactive as predicted by the missing-self hypothesis. As a result, it is unclear if MHC-I down-regulation in vivo induces NK cell reactivity or tolerance to missing-self. Here, we generated a floxed B2m mouse to acutely down-regulate MHC-I in vivo in a host that normally expresses MHC-I. Global down-regulation of MHC-I induced NK cell hyporesponsiveness and tolerance to missing-self without overt missing-self reactivity. In contrast, down-regulation of MHC-I on a small fraction of hematopoietic cells triggered missing-self reactivity. Surprisingly, down-regulation of MHC-I only on CD4 + T cells predominately induced tolerance to missing-self without resetting NK cell responsiveness. In this setting, inflammation triggered substantial missing-self reactivity. These results show that MHC-I down-regulation can induce either NK cell tolerance or killing in vivo and that inflammation promotes missing-self reactivity.
UR - http://www.scopus.com/inward/record.url?scp=85059928703&partnerID=8YFLogxK
U2 - 10.1084/jem.20181076
DO - 10.1084/jem.20181076
M3 - Article
C2 - 30559128
AN - SCOPUS:85059928703
SN - 0022-1007
VL - 216
SP - 99
EP - 116
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -