PMID- 27895176
OWN - NLM
STAT- MEDLINE
DCOM- 20170808
LR  - 20181113
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 198
IP  - 1
DP  - 2017 Jan 1
TI  - The Syk-NFAT-IL-2 Pathway in Dendritic Cells Is Required for Optimal Sterile 
      Immunity Elicited by Alum Adjuvants.
PG  - 196-204
AB  - Despite a long history and extensive usage of insoluble aluminum salts (alum) as 
      vaccine adjuvants, the molecular mechanisms underpinning Ag-specific immunity 
      upon vaccination remain unclear. Dendritic cells (DCs) are crucial initiators of 
      immune responses, but little is known about the molecular pathways used by DCs to 
      sense alum and, in turn, activate T and B cells. In this article, we show that 
      alum adjuvanticity requires IL-2 specifically released by DCs, even when T cell 
      secretion of IL-2 is intact. We demonstrate that alum, as well as other sterile 
      particulates, such as uric acid crystals, induces DCs to produce IL-2 following 
      initiation of actin-mediated phagocytosis that leads to Src and Syk kinase 
      activation, Ca(2+) mobilization, and calcineurin-dependent activation of NFAT, 
      the master transcription factor regulating IL-2 expression. Using chimeric mice, 
      we show that DC-derived IL-2 is required for maximal Ag-specific proliferation of 
      CD4(+) T cells and optimal humoral responses following alum-adjuvanted 
      immunization. These data identify DC-derived IL-2 as a key mediator of alum 
      adjuvanticity in vivo and the Src-Syk pathway as a potential leverage point in 
      the rational design of novel adjuvants.
CI  - Copyright (c) 2016 by The American Association of Immunologists, Inc.
FAU - Khameneh, Hanif Javanmard
AU  - Khameneh HJ
AUID- ORCID: 0000-0002-1737-0388
AD  - Singapore Immunology Network (SIgN), Agency for Science, Technology and Research 
      (A*STAR), Singapore 138648, Singapore.
FAU - Ho, Adrian W S
AU  - Ho AW
AD  - Singapore Immunology Network (SIgN), Agency for Science, Technology and Research 
      (A*STAR), Singapore 138648, Singapore.
FAU - Spreafico, Roberto
AU  - Spreafico R
AD  - Singapore Immunology Network (SIgN), Agency for Science, Technology and Research 
      (A*STAR), Singapore 138648, Singapore.
FAU - Derks, Heidi
AU  - Derks H
AUID- ORCID: 0000-0002-1156-4106
AD  - Singapore Immunology Network (SIgN), Agency for Science, Technology and Research 
      (A*STAR), Singapore 138648, Singapore.
FAU - Quek, Hazel Q Y
AU  - Quek HQ
AUID- ORCID: 0000-0001-5597-5372
AD  - Singapore Immunology Network (SIgN), Agency for Science, Technology and Research 
      (A*STAR), Singapore 138648, Singapore.
FAU - Mortellaro, Alessandra
AU  - Mortellaro A
AUID- ORCID: 0000-0003-1744-2430
AD  - Singapore Immunology Network (SIgN), Agency for Science, Technology and Research 
      (A*STAR), Singapore 138648, Singapore 
      alessandra_mortellaro@immunol.a-star.edu.sg.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20161128
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Alum Compounds)
RN  - 0 (Interleukin-2)
RN  - 0 (NFATC Transcription Factors)
RN  - 34S289N54E (aluminum sulfate)
RN  - EC 2.7.10.2 (Syk Kinase)
SB  - IM
MH  - Adjuvants, Immunologic/*pharmacology
MH  - Alum Compounds/*pharmacology
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - Dendritic Cells/*immunology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flow Cytometry
MH  - Interleukin-2/immunology
MH  - Lymphocyte Activation/drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Models, Animal
MH  - NFATC Transcription Factors/immunology
MH  - Signal Transduction/drug effects/*immunology
MH  - Syk Kinase/immunology
PMC - PMC5164880
EDAT- 2016/11/30 06:00
MHDA- 2017/08/09 06:00
PMCR- 2016/11/28
CRDT- 2016/11/30 06:00
PHST- 2016/03/10 00:00 [received]
PHST- 2016/10/28 00:00 [accepted]
PHST- 2016/11/30 06:00 [pubmed]
PHST- 2017/08/09 06:00 [medline]
PHST- 2016/11/30 06:00 [entrez]
PHST- 2016/11/28 00:00 [pmc-release]
AID - jimmunol.1600420 [pii]
AID - ji_1600420 [pii]
AID - 10.4049/jimmunol.1600420 [doi]
PST - ppublish
SO  - J Immunol. 2017 Jan 1;198(1):196-204. doi: 10.4049/jimmunol.1600420. Epub 2016 
      Nov 28.