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The Journal of Immunology is published twice each month by
The American Association of Immunologists, Inc.,
1451 Rockville Pike, Suite 650, Rockville, MD 20852
Copyright © 2017 by The American Association of
Immunologists, Inc. All rights reserved.
Print ISSN: 0022-1767 Online ISSN: 1550-6606.
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J Immunol 2017; 198:555-556; ;
doi: 10.4049/jimmunol.1690023
http://www.jimmunol.org/content/198/2/555
The
In This Issue
RvD2/DRV2 Squelch Sepsis
S
TGF-b Boosts Kidney TRM Cells
T
issue-resident memory T (TRM) cells are noncirculating
T cells that reside either in barrier tissues, such as the
gut (CD691CD1031 and CD691CD1032 TRM) or
nonbarrier tissues, such as the kidney (CD691CD1032 TRM).
Whereas TGF-b is known to be required for the differentiation of
CD691CD1031 TRM cells in barrier tissues, its role in developmental control of TRM in nonbarrier tissues remains unknown.
Upregulation of signals such as CXCR3 that facilitate transendothelial migration is key for the differentiation of TRM in
nonbarrier tissues, but it is not clear whether TGF-b is involved
in modulating these signals. In this issue, Ma et al. (p. 749) ex-
Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1690023
Immunology
amined the molecular mechanisms that control the generation
of kidney-resident TRM cells by employing a model in which
congenically marked P14 TCR transgenic CD81 T cells specific
for the lymphocytic choriomeningitis virus (LCMV) glycoprotein
were transferred into unmanipulated mice that were then subjected to acute LCMV infection. Although both kidney-resident
and blood-borne donor–derived P14 T cells were identified in the
kidney following LCMV infection, only the kidney-resident P14
T cells upregulated CD69 and CXCR3 to become TRM T cells.
Suggesting a role for TGF-b in transendothelial migration of
effector T cells, adoptive transfer of donor P14 T cells that were
unresponsive to TGF-b (Tgfbr22/2) resulted in significantly decreased P14 cell numbers in the kidney, but not in the blood,
12 d postinfection. In addition, these Tgfbr22/2 P14 T cells
showed decreased expression of ligands for E- and P-selectin,
which appeared to be dependent on O-glycosylation of selectin
ligands by Glucosaminyl [N-Acetyl] Transferase 1, core 2
(Gcnt1), as expression of Gcnt1 was significantly reduced in naive
T cells isolated from Tgfbr22/2 mice. Retroviral transduction of
Gcnt1 into donor Tgfbr22/2 P14 T cells not only rescued the
expression of E- and P-selectin ligands to control levels, but also
increased the accumulation of donor Tgfbr22/2 T cells in the
kidney of recipient mice following LCMV infection. Furthermore, TGF-b appeared to enhance the expression of CXCR3 on
effector T cells, as donor Tgfbr22/2 P14 T cells recovered from
LCMV-infected recipients showed reduced CXCR3 expression
and donor P14 T cells deficient in CXCR3 failed to accumulate
in the kidneys of LCMV-infected animals. Taken together, these
data demonstrate that TGF-b promotes O-glycan synthesis and
the expression of CXCR3, demonstrating that TGF-b enhances
the extravasation of effector CD81 T cells into the kidney,
thereby controlling the first developmental step in the generation
of TRM T cells in nonbarrier tissues.
A Null Allele of MPYS
C
ytosolic sensors of cyclic
dinucleotides (CDNs) are
important for host defense
against viral and bacterial infections and are also involved in autoinflammatory diseases and cancer.
The second most common allele of
the human TMEM173 gene, which encodes the CDN sensor
MPYS, is designated as HAQ for the three single-nucleotide
polymorphisms (SNPs) that distinguish it from the more
common R232 allele. In this issue, Patel et al. (p. 776) examined the function of the HAQ allele of TMEM173 relative to R232, determining that HAQ is a null allele. After
cataloguing how the presence of HAQ varies among different
ethnicities, the authors found that B cells from individuals homozygous for the HAQ allele expressed very little
MPYS protein and also showed reduced levels of TMEM173
mRNA. Consistent with this observation, these B cells did not
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pecialized proresolving mediators including resolvins
actively contribute to the
resolution of inflammation. A better understanding of this process
could lead to effective treatments
for polymicrobial sepsis, which has
a high mortality rate. In this issue,
Chiang et al. (p. 842) investigated a
potential role for the interaction
between resolvin D2 (RvD2) and
its receptor, DRV2, in the resolution of inflammation caused by
systemic infection. Intraperitoneal
administration of RvD2 to wild-type (WT) mice subjected to
cecal ligation and puncture (CLP) increased survival, reduced
hypothermia, and increased bacterial killing relative to controls,
whereas these protective effects were not seen in RvD2-treated
DRV2-knockout (DRV2-KO) mice. Mass spectrometry–based
metabololipidomic analysis of infectious exudates from CLPtreated WT versus DRV2-KO mice revealed increased proinflammatory lipid mediators and decreased proresolving molecules
in DRV2-KO mice, and proteome profiling indicated that RvD2
treatment of WT, but not DRV2-KO, mice promoted upregulation of proteins with protective roles in infection. Using mass
cytometry to probe the mechanism of RvD2-DRV2–mediated
suppression of infectious inflammation, the authors identified
several kinases and transcription factors that were activated following RvD2 treatment of macrophages. In particular, activation
of the STAT3 and cAMP–PKA pathways was important for the
enhancement of phagocytosis of live E. coli induced by RvD2
treatment of WT, but not DRV2 KO, macrophages. Taken together, these data describe signaling pathways by which RvD2 acts
through DRV2 to increase bacterial clearance and reduce mortality in sepsis, which may provide avenues for research into future
treatments for septic inflammation.
Journal of
556
respond to naturally occurring or synthetically derived CDNs,
unlike B cells from individuals bearing the R232 allele. B cells
from individuals bearing an H232 allele also demonstrated
defective responses to CDNs. To analyze the activity of the
HAQ allele in vivo, the authors generated a mouse model
bearing the murine equivalent of the HAQ mutations and
found that B cells in these mHAQ mice had reduced expression of MPYS, as did T cells, monocytes, and dendritic
cells. Similar to human B cells bearing the HAQ allele, bone
marrow–derived macrophages and dendritic cells from mHAQ
IN THIS ISSUE
mice failed to respond to CDNs. In vivo analysis revealed
that mHAQ mice did not mount responses in the lung
to CDNs, which are used as mucosal adjuvants, and the
Pneumovax 23 vaccine, which depends on MPYS activation
for activity, was less protective in mHAQ relative to wildtype mice. Further understanding of the effects of this
common null allele on human health will be important,
as MPYS is important for protection against bacterial and
viral infections and is being investigated as a target for
immunotherapy.
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The Journal of Immunology
2513
Corrections
In This Issue. 2017. J. Immunol. 198: 555–556.
In the third summary, titled “A Null Allele of MPYS,” an error was made in the description of the H232 allele. The sixth sentence
should read “B cells from individuals bearing an H232 allele also demonstrated defective responses to CDNs.”
The online version has been changed to reflect this correction and, as such, differs from the print version.
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700130
Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00