RvD2/DRV2 Squelch Sepsis
Specialized 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 CLP-treated 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.
TGF-β Boosts Kidney TRM Cells
Tissue-resident memory T (TRM) cells are noncirculating T cells that reside either in barrier tissues, such as the gut (CD69+CD103+ and CD69+CD103− TRM) or nonbarrier tissues, such as the kidney (CD69+CD103− TRM). Whereas TGF-β is known to be required for the differentiation of CD69+CD103+ 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-β is involved in modulating these signals. In this issue, Ma et al. (p. 749) examined the molecular mechanisms that control the generation of kidney-resident TRM cells by employing a model in which congenically marked P14 TCR transgenic CD8+ 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-β in transendothelial migration of effector T cells, adoptive transfer of donor P14 T cells that were unresponsive to TGF-β (Tgfbr2−/−) resulted in significantly decreased P14 cell numbers in the kidney, but not in the blood, 12 d postinfection. In addition, these Tgfbr2−/− 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 Tgfbr2−/− mice. Retroviral transduction of Gcnt1 into donor Tgfbr2−/− P14 T cells not only rescued the expression of E- and P-selectin ligands to control levels, but also increased the accumulation of donor Tgfbr2−/− T cells in the kidney of recipient mice following LCMV infection. Furthermore, TGF-β appeared to enhance the expression of CXCR3 on effector T cells, as donor Tgfbr2−/− 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-β promotes O-glycan synthesis and the expression of CXCR3, demonstrating that TGF-β enhances the extravasation of effector CD8+ 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
Cytosolic 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 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 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 wild-type 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.
- Copyright © 2017 by The American Association of Immunologists, Inc.