PMID- 26810223
OWN - NLM
STAT- MEDLINE
DCOM- 20160802
LR  - 20181113
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 196
IP  - 5
DP  - 2016 Mar 1
TI  - Ptpn22 Modifies Regulatory T Cell Homeostasis via GITR Upregulation.
PG  - 2145-52
LID - 10.4049/jimmunol.1501877 [doi]
AB  - PTPN22 gene variation associates with multiple autoimmune diseases, including 
      type 1 diabetes and rheumatoid arthritis. Loss of function studies have 
      demonstrated that PTPN22 impinges on the homeostatic behavior of regulatory T 
      (Treg) cells, a lineage critical for immune tolerance. The frequency and absolute 
      number of Treg cells is increased in Ptpn22-deficient mice, but the mechanism 
      driving this increase is unknown. In this study, we show that Ptpn22 knockdown 
      (KD) promoted the expansion of the Treg cell compartment by upregulating the 
      glucocorticoid-induced TNFR family-related protein (GITR) and increasing GITR 
      signaling. Ptpn22 KD did not accelerate cell division but instead prolonged Treg 
      cell survival, as measured by a decrease in the frequency of apoptotic Treg 
      cells. Loss of Ptpn22 caused a concomitant increase in the proportion of 
      CD44(hi)CD62L(lo) effector Treg cells, at the expense of CD44(lo)CD62L(hi) 
      central Treg cells. The increase in Treg cell numbers, but not their 
      differentiation toward an effector phenotype, was dependent on GITR signaling, 
      because blockade of GITR ligand prevented Treg cell expansion caused by Ptpn22 
      KD. These findings indicate that GITR plays a key role in regulating the overall 
      size of the Treg cell pool. Our results suggest that the size and composition of 
      the Treg cell compartment are independently controlled and have implications for 
      the design of immunotherapies that seek to improve Treg cell function.
CI  - Copyright (c) 2016 by The American Association of Immunologists, Inc.
FAU - Nowakowska, Dominika J
AU  - Nowakowska DJ
AD  - Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215.
FAU - Kissler, Stephan
AU  - Kissler S
AD  - Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215 
      Stephan.Kissler@joslin.harvard.edu.
LA  - eng
GR  - P30 DK036836/DK/NIDDK NIH HHS/United States
GR  - P30DK036836/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 - 20160125
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Glucocorticoid-Induced TNFR-Related Protein)
RN  - 0 (Tnfrsf18 protein, mouse)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 22)
RN  - EC 3.1.3.48 (Ptpn22 protein, mouse)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Flow Cytometry
MH  - Gene Expression Regulation/*immunology
MH  - Gene Knockdown Techniques
MH  - Glucocorticoid-Induced TNFR-Related Protein/*immunology
MH  - Homeostasis/*immunology
MH  - Immune Tolerance/immunology
MH  - Mice
MH  - Mice, Transgenic
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 22/*immunology
MH  - T-Lymphocytes, Regulatory/*immunology
MH  - Up-Regulation
PMC - PMC4761465
MID - NIHMS748665
EDAT- 2016/01/27 06:00
MHDA- 2016/08/03 06:00
PMCR- 2017/03/01
CRDT- 2016/01/27 06:00
PHST- 2015/08/20 00:00 [received]
PHST- 2015/12/28 00:00 [accepted]
PHST- 2017/03/01 00:00 [pmc-release]
PHST- 2016/01/27 06:00 [entrez]
PHST- 2016/01/27 06:00 [pubmed]
PHST- 2016/08/03 06:00 [medline]
AID - jimmunol.1501877 [pii]
AID - 10.4049/jimmunol.1501877 [doi]
PST - ppublish
SO  - J Immunol. 2016 Mar 1;196(5):2145-52. doi: 10.4049/jimmunol.1501877. Epub 2016 
      Jan 25.