PMID- 24038092
OWN - NLM
STAT- MEDLINE
DCOM- 20131210
LR  - 20220311
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 191
IP  - 8
DP  - 2013 Oct 15
TI  - Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T 
      cells and promotes skin allograft survival.
PG  - 4447-55
LID - 10.4049/jimmunol.1300992 [doi]
AB  - Dendritic cells (DCs) are the central architects of the immune response, inducing 
      inflammatory or tolerogenic immunity, dependent on their activation status. As 
      such, DCs are highly attractive therapeutic targets and may hold the potential to 
      control detrimental immune responses. TIM-4, expressed on APCs, has complex 
      functions in vivo, acting both as a costimulatory molecule and a 
      phosphatidylserine receptor. The effect of TIM-4 costimulation on T cell 
      activation remains unclear. In this study, we demonstrate that Ab blockade of 
      DC-expressed TIM-4 leads to increased induction of induced regulatory T cells 
      (iTregs) from naive CD4(+) T cells, both in vitro and in vivo. iTreg induction 
      occurs through suppression of IL-4/STAT6/Gata3-induced Th2 differentiation. In 
      addition, blockade of TIM-4 on previously activated DCs still leads to increased 
      iTreg induction. iTregs induced under TIM-4 blockade have equivalent potency to 
      control and, upon adoptive transfer, significantly prolong skin allograft 
      survival in vivo. In RAG(-/-) recipients of skin allografts adoptively 
      transferred with CD4(+) T cells, we show that TIM-4 blockade in vivo is 
      associated with a 3-fold prolongation in allograft survival. Furthermore, in this 
      mouse model of skin transplantation, increased induction of allospecific iTregs 
      and a reduction in T effector responses were observed, with decreased Th1 and Th2 
      responses. This enhanced allograft survival and protolerogenic skewing of the 
      alloresponse is critically dependent on conversion of naive CD4(+) to Tregs in 
      vivo. Collectively, these studies identify blockade of DC-expressed TIM-4 as a 
      novel strategy that holds the capacity to induce regulatory immunity in vivo.
FAU - Yeung, Melissa Y
AU  - Yeung MY
AD  - Transplantation Research Center, Renal Division, Brigham and Women's Hospital, 
      Harvard Medical School, Boston, MA 02445;
FAU - McGrath, Martina M
AU  - McGrath MM
FAU - Nakayama, Masafumi
AU  - Nakayama M
FAU - Shimizu, Tetsunosuke
AU  - Shimizu T
FAU - Boenisch, Olaf
AU  - Boenisch O
FAU - Magee, Ciara N
AU  - Magee CN
FAU - Abdoli, Rozita
AU  - Abdoli R
FAU - Akiba, Hisaya
AU  - Akiba H
FAU - Ueno, Takuya
AU  - Ueno T
FAU - Turka, Laurence A
AU  - Turka LA
FAU - Najafian, Nader
AU  - Najafian N
LA  - eng
GR  - R56 AI101150/AI/NIAID NIH HHS/United States
GR  - R56 AI089777/AI/NIAID NIH HHS/United States
GR  - R56 AI101150-0141/AI/NIAID NIH HHS/United States
GR  - R01 AI037691/AI/NIAID NIH HHS/United States
GR  - R01AI037691-17A1/AI/NIAID NIH HHS/United States
GR  - R56AI089777-01A1/AI/NIAID NIH HHS/United States
GR  - T32 DK007527/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130913
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (GATA3 Transcription Factor)
RN  - 0 (Gata3 protein, mouse)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (STAT6 Transcription Factor)
RN  - 0 (Stat6 protein, mouse)
RN  - 0 (TIM-4 protein, mouse)
RN  - 128559-51-3 (RAG-1 protein)
RN  - 207137-56-2 (Interleukin-4)
SB  - IM
MH  - Adoptive Transfer
MH  - Allografts/immunology
MH  - Animals
MH  - Antibodies, Monoclonal/immunology
MH  - Cell Differentiation/immunology
MH  - Cells, Cultured
MH  - Dendritic Cells/*immunology
MH  - GATA3 Transcription Factor/immunology
MH  - *Graft Survival
MH  - Homeodomain Proteins/genetics
MH  - Interleukin-4/immunology
MH  - Lymphocyte Activation
MH  - Membrane Proteins/immunology/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - STAT6 Transcription Factor/immunology
MH  - Signal Transduction
MH  - *Skin Transplantation
MH  - T-Lymphocytes, Regulatory/*immunology/metabolism
MH  - Th1 Cells/immunology
MH  - Th2 Cells/immunology
PMC - PMC3804420
MID - NIHMS515004
EDAT- 2013/09/17 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/10/15
CRDT- 2013/09/17 06:00
PHST- 2013/09/17 06:00 [entrez]
PHST- 2013/09/17 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/10/15 00:00 [pmc-release]
AID - jimmunol.1300992 [pii]
AID - 10.4049/jimmunol.1300992 [doi]
PST - ppublish
SO  - J Immunol. 2013 Oct 15;191(8):4447-55. doi: 10.4049/jimmunol.1300992. Epub 2013 
      Sep 13.