PMID- 30006377
OWN - NLM
STAT- MEDLINE
DCOM- 20190709
LR  - 20190709
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 201
IP  - 4
DP  - 2018 Aug 15
TI  - Effector T Cell Resistance to Suppression and STAT3 Signaling during the
      Development of Human Type 1 Diabetes.
PG  - 1144-1153
LID - 10.4049/jimmunol.1701199 [doi]
AB  - Dysregulation of regulatory T cell (Treg)-mediated suppression and, in
      particular, resistance of CD4(+) effector T cells (Teffs) to suppression have
      been implicated in the pathogenesis of human type 1 diabetes (T1D). However, the 
      mechanistic basis behind this resistance and the time frame during which it
      develops in relation to the onset of clinical T1D remain unclear. In this study, 
      we analyzed the capacity of peripheral blood Teffs isolated both from patients
      with T1D and from prediabetic at-risk subjects positive for multiple
      diabetes-associated autoantibodies (AAb(+)) to be suppressed by Tregs. Because
      STAT3 activation through IL-6 has previously been implicated in mediating Teff
      resistance, we also investigated the surface expression of IL-6R as well as IL-6-
      and TCR-mediated phosphorylation of STAT3 in T cells from our study subjects.
      Teff resistance to suppression was observed both in patients with newly diagnosed
      and long-standing T1D but not in AAb(+) subjects and was shown to be STAT3
      dependent. No alterations in IL-6R expression or IL-6-mediated STAT3 activation
      were observed in T cells from patients with T1D or AAb(+) subjects. However,
      faster STAT3 activation after TCR stimulation without concomitant increase in
      IL-6 expression was observed in T cells from patients with T1D. These experiments
      suggest that Teff resistance in T1D patients is STAT3 dependent but not directly 
      linked with the capacity of Teffs to produce or respond to IL-6. In conclusion,
      Teff resistance to Treg-mediated suppression is likely a feature of disease
      progression in human T1D and can potentially be targeted by immune therapies that
      block STAT3 activation.
CI  - Copyright (c) 2018 by The American Association of Immunologists, Inc.
FAU - Ihantola, Emmi-Leena
AU  - Ihantola EL
AD  - Department of Clinical Microbiology, Institute of Clinical Medicine, University
      of Eastern Finland, 70210 Kuopio, Finland.
FAU - Viisanen, Tyyne
AU  - Viisanen T
AD  - Department of Clinical Microbiology, Institute of Clinical Medicine, University
      of Eastern Finland, 70210 Kuopio, Finland.
FAU - Gazali, Ahmad M
AU  - Gazali AM
AUID- ORCID: 0000-0001-7705-3408
AD  - Department of Clinical Microbiology, Institute of Clinical Medicine, University
      of Eastern Finland, 70210 Kuopio, Finland.
FAU - Nanto-Salonen, Kirsti
AU  - Nanto-Salonen K
AUID- ORCID: 0000-0002-6035-966X
AD  - Department of Pediatrics, Turku University Hospital, 20521 Turku, Finland.
FAU - Juutilainen, Auni
AU  - Juutilainen A
AD  - Department of Medicine, Kuopio University Hospital, 70210 Kuopio, Finland.
AD  - Institute of Clinical Medicine, University of Eastern Finland, 70210 Kuopio,
      Finland.
FAU - Moilanen, Leena
AU  - Moilanen L
AD  - Department of Medicine, Kuopio University Hospital, 70210 Kuopio, Finland.
FAU - Rintamaki, Reeta
AU  - Rintamaki R
AD  - Department of Medicine, Kuopio University Hospital, 70210 Kuopio, Finland.
FAU - Pihlajamaki, Jussi
AU  - Pihlajamaki J
AD  - Institute of Public Health and Clinical Nutrition, University of Eastern Finland,
      70210 Kuopio, Finland.
AD  - Clinical Nutrition and Obesity Center, Kuopio University Hospital, 70210 Kuopio, 
      Finland.
FAU - Veijola, Riitta
AU  - Veijola R
AD  - Department of Pediatrics, Medical Research Center, PEDEGO Research Unit, Oulu
      University Hospital and University of Oulu, 90014 Oulu, Finland.
FAU - Toppari, Jorma
AU  - Toppari J
AUID- ORCID: 0000-0003-2228-334X
AD  - Department of Pediatrics, Turku University Hospital, 20521 Turku, Finland.
AD  - Department of Physiology, Institute of Biomedicine, University of Turku, 20520
      Turku, Finland.
FAU - Knip, Mikael
AU  - Knip M
AUID- ORCID: 0000-0003-0474-0033
AD  - Tampere Center for Child Health Research, Tampere University Hospital, 33521
      Tampere, Finland.
AD  - Children's Hospital, University of Helsinki and Helsinki University Hospital,
      00281 Helsinki, Finland.
AD  - Research Programs Unit - Diabetes and Obesity, University of Helsinki, 00290
      Helsinki, Finland.
AD  - Folkhalsan Research Center, 00290 Helsinki, Finland.
FAU - Ilonen, Jorma
AU  - Ilonen J
AUID- ORCID: 0000-0002-9973-2062
AD  - Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, 20520
      Turku, Finland.
AD  - Department of Clinical Microbiology, Turku University Hospital, 20520 Turku,
      Finland; and.
FAU - Kinnunen, Tuure
AU  - Kinnunen T
AUID- ORCID: 0000-0003-1595-5371
AD  - Department of Clinical Microbiology, Institute of Clinical Medicine, University
      of Eastern Finland, 70210 Kuopio, Finland; tuure.kinnunen@uef.fi.
AD  - Eastern Finland Laboratory Centre, 70210 Kuopio, Finland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180713
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (STAT3 Transcription Factor)
SB  - AIM
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Antibody Formation
MH  - Cells, Cultured
MH  - Child
MH  - Child, Preschool
MH  - Cohort Studies
MH  - Diabetes Mellitus, Type 1/*immunology
MH  - Female
MH  - Humans
MH  - Immune Tolerance
MH  - Male
MH  - Middle Aged
MH  - Phosphorylation
MH  - STAT3 Transcription Factor/*metabolism
MH  - Signal Transduction
MH  - T-Lymphocytes, Regulatory/*immunology
MH  - Young Adult
EDAT- 2018/07/15 06:00
MHDA- 2019/07/10 06:00
CRDT- 2018/07/15 06:00
PHST- 2017/08/21 00:00 [received]
PHST- 2018/06/09 00:00 [accepted]
PHST- 2018/07/15 06:00 [pubmed]
PHST- 2019/07/10 06:00 [medline]
PHST- 2018/07/15 06:00 [entrez]
AID - jimmunol.1701199 [pii]
AID - 10.4049/jimmunol.1701199 [doi]
PST - ppublish
SO  - J Immunol. 2018 Aug 15;201(4):1144-1153. doi: 10.4049/jimmunol.1701199. Epub 2018
      Jul 13.