PMID- 31980486
OWN - NLM
STAT- MEDLINE
DCOM- 20201009
LR  - 20220107
IS  - 2470-9468 (Electronic)
IS  - 2470-9468 (Linking)
VI  - 5
IP  - 43
DP  - 2020 Jan 24
TI  - Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell 
      differentiation.
LID - 10.1126/sciimmunol.aaz0085 [doi]
LID - eaaz0085
AB  - T follicular helper cells (T(FH)) participate in germinal center (GC) development 
      and are necessary for B cell production of high-affinity, isotype-switched 
      antibodies. In a forward genetic screen, we identified a missense mutation in 
      Prkd2, encoding the serine/threonine kinase protein kinase D2, which caused 
      elevated titers of immunoglobulin E (IgE) in the serum. Subsequent analysis of 
      serum antibodies in mice with a targeted null mutation of Prkd2 demonstrated 
      polyclonal hypergammaglobulinemia of IgE, IgG1, and IgA isotypes, which was 
      exacerbated by the T cell-dependent humoral response to immunization. GC 
      formation and GC B cells were increased in Prkd2(-/-) spleens. These effects were 
      the result of excessive cell-autonomous T(FH) development caused by unrestricted 
      Bcl6 nuclear translocation in Prkd2(-/-) CD4(+) T cells. Prkd2 directly binds to 
      Bcl6, and Prkd2-dependent phosphorylation of Bcl6 is necessary to constrain Bcl6 
      to the cytoplasm, thereby limiting T(FH) development. In response to 
      immunization, Bcl6 repressed Prkd2 expression in CD4(+) T cells, thereby 
      committing them to T(FH) development. Thus, Prkd2 and Bcl6 form a mutually 
      inhibitory positive feedback loop that controls the stable transition from naive 
      CD4(+) T cells to T(FH) during the adaptive immune response.
CI  - Copyright (c) 2020 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Misawa, Takuma
AU  - Misawa T
AUID- ORCID: 0000-0003-4642-6229
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA. takuma.misawa@utsouthwestern.edu bruce.beutler@utsouthwestern.edu.
FAU - SoRelle, Jeffrey A
AU  - SoRelle JA
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Choi, Jin Huk
AU  - Choi JH
AUID- ORCID: 0000-0003-2483-4379
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Yue, Tao
AU  - Yue T
AUID- ORCID: 0000-0001-5417-2826
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Wang, Kuan-Wen
AU  - Wang KW
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - McAlpine, William
AU  - McAlpine W
AUID- ORCID: 0000-0002-4611-5968
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Wang, Jianhui
AU  - Wang J
AUID- ORCID: 0000-0002-6335-8355
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Liu, Aijie
AU  - Liu A
AUID- ORCID: 0000-0002-4777-7795
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Tabeta, Koichi
AU  - Tabeta K
AUID- ORCID: 0000-0002-7019-1872
AD  - Division of Periodontology, Department of Oral Biological Science, Niigata 
      University Graduate School of Medical and Dental Science, Niigata, Japan.
FAU - Turer, Emre E
AU  - Turer EE
AUID- ORCID: 0000-0001-8782-3648
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Evers, Bret
AU  - Evers B
AUID- ORCID: 0000-0001-5686-0315
AD  - Division of Neuropathology, UT Southwestern Medical Center, Dallas, TX 75390, 
      USA.
FAU - Nair-Gill, Evan
AU  - Nair-Gill E
AUID- ORCID: 0000-0002-9876-7853
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Poddar, Subhajit
AU  - Poddar S
AUID- ORCID: 0000-0002-9764-3242
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Su, Lijing
AU  - Su L
AUID- ORCID: 0000-0003-1533-0988
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Ou, Feiya
AU  - Ou F
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Yu, Liyang
AU  - Yu L
AUID- ORCID: 0000-0002-7337-4420
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Russell, Jamie
AU  - Russell J
AUID- ORCID: 0000-0002-9090-4067
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Ludwig, Sara
AU  - Ludwig S
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Zhan, Xiaoming
AU  - Zhan X
AUID- ORCID: 0000-0003-2045-5259
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Hildebrand, Sara
AU  - Hildebrand S
AUID- ORCID: 0000-0002-5534-3604
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Li, Xiaohong
AU  - Li X
AUID- ORCID: 0000-0001-8357-5587
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Tang, Miao
AU  - Tang M
AUID- ORCID: 0000-0002-8708-3296
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Murray, Anne R
AU  - Murray AR
AUID- ORCID: 0000-0002-5586-635X
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Moresco, Eva Marie Y
AU  - Moresco EMY
AUID- ORCID: 0000-0002-2049-7291
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA.
FAU - Beutler, Bruce
AU  - Beutler B
AUID- ORCID: 0000-0002-3639-246X
AD  - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, 
      TX 75390, USA. takuma.misawa@utsouthwestern.edu bruce.beutler@utsouthwestern.edu.
LA  - eng
GR  - T32 AI005284/AI/NIAID NIH HHS/United States
GR  - R01 DK119360/DK/NIDDK NIH HHS/United States
GR  - U19 AI100627/AI/NIAID NIH HHS/United States
GR  - R01 AI125581/AI/NIAID NIH HHS/United States
GR  - K08 DK107886/DK/NIDDK NIH HHS/United States
GR  - U01 AI095542/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Immunol
JT  - Science immunology
JID - 101688624
RN  - 0 (Bcl6 protein, mouse)
RN  - 0 (Immunoglobulins)
RN  - 0 (Protein Kinase D2)
RN  - 0 (Proto-Oncogene Proteins c-bcl-6)
RN  - EC 2.7.- (Protein Kinases)
SB  - IM
MH  - Animals
MH  - B-Lymphocytes/immunology
MH  - Bone Marrow Transplantation
MH  - CD4-Positive T-Lymphocytes/*immunology
MH  - Cell Differentiation
MH  - Female
MH  - Germinal Center/immunology
MH  - HEK293 Cells
MH  - Humans
MH  - Immunoglobulins/blood
MH  - Immunotherapy, Adoptive
MH  - Male
MH  - Mice, Transgenic
MH  - Mutation
MH  - Protein Kinase D2
MH  - Protein Kinases/genetics/*immunology
MH  - Proto-Oncogene Proteins c-bcl-6/*immunology
PMC - PMC7278039
MID - NIHMS1585418
EDAT- 2020/01/26 06:00
MHDA- 2020/10/10 06:00
PMCR- 2020/07/24
CRDT- 2020/01/26 06:00
PHST- 2019/08/05 00:00 [received]
PHST- 2020/01/06 00:00 [accepted]
PHST- 2020/01/26 06:00 [entrez]
PHST- 2020/01/26 06:00 [pubmed]
PHST- 2020/10/10 06:00 [medline]
PHST- 2020/07/24 00:00 [pmc-release]
AID - 5/43/eaaz0085 [pii]
AID - 10.1126/sciimmunol.aaz0085 [doi]
PST - ppublish
SO  - Sci Immunol. 2020 Jan 24;5(43):eaaz0085. doi: 10.1126/sciimmunol.aaz0085.