CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways

Wein, Alexander N.; McMaster, Sean R.; Takamura, Shiki; Dunbar, P. Rod; Cartwright, Emily K.; Hayward, Sarah L.; McManus, Daniel; Shimaoka, Takeshi; Ueha, Satoshi; Tsukui, Tohru; Masumoto, Tomoko; Kurachi, Makoto; Matsushima, Kouji; Kohlmeier, Jacob E.

doi:10.1084/jem.20181308

Cited by 226 publications

(244 citation statements)

References 41 publications

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“…We provide evidence that Aim2 might operate by suppressing CXCL16 expression by B cells. These data are consistent with the previously established role of CXCL16 and its receptor, CXCR6, in regulating CD8 + Trm cells (45), in addition to CXCR6 being one of the defining markers of CD8 + Trm cells (46).…”

Section: Discussionsupporting

confidence: 92%

Aim2-mediated/IFN-β–independent regulation of gastric metaplastic lesions via CD8+ T cells

El–Zaatari¹,

Bishu²,

Zhang³

et al. 2020

JCI Insight

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Aim2 deletion exacerbates SPEM. We identified Aim2 in a screen of upregulated gastric genes in 2 mouse models of SPEM: (a) chronic (6-month) H. felis infection and (b) gastric tissue-specific overexpression of IFN-γ (H + / K +-ATPase-IFN-γ) (18) (Figure 1A). The upregulation of Aim2 in gastric tissue of chronically H. felis-infected mice at 6 months was corroborated by real-time quantitative PCR (RT-qPCR) (Figure 1B). To study the role of Aim2 in SPEM, we used mice deficient in Aim2 (B6.129P2-Aim2 Gt(CSG445)Byg /J; Aim2-/-) and chronically infected them with H. felis. We confirmed that Aim2 deletion abrogated Aim2 expression in the stomach (Figure 1B). Aim2 deficiency worsened gastric immunopathology (Figure 1C), increased stomach weight (Figure 1D), exacerbated SPEM (Figure 1, E and F), and enhanced parietal cell atrophy (Figure 1G). All the latter characteristics epitomize features of enhanced gastric preneoplastic development in Aim2-/mice. Aim2 lacks a significant effect on gastric inflammasome activity. Because Aim2 functions as a component of the inflammasome (13-15), we investigated whether Aim2 was mediating its observed effects by regulating IL-1β and IL-18 secretion. We found gastric explants from 6-month infected Aim2-/stomachs did not show a significant effect on the secretion of IL-1β or IL-18 (Supplemental Figure 1, A and B; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.94035DS1). Hence, these observations did not provide mechanistic insight into how the loss of Aim2 led to increased SPEM. This prompted us to dissect the mechanism of how Aim2 inhibits SPEM further. Aim2 is not required for the expression of the inhibitory Fcγ receptor. Because a previous report showed that Aim2 is necessary for the expression of the inhibitory Fcγ receptor (FcγRIIB) (19), we investigated a possible alternative mechanism for Aim2 via this protein. FcγRIIB is a lupus susceptibility protein that suppresses antibody production in B cells (20) and blocks maturation of dendritic cells (21). However, we did not observe a significant effect of Aim2 deficiency on FcγRIIB expression in the inflamed stomach (Supplemental Figure 1C). Aim2 deficiency increases gastric CD8 + T cell frequency in the chronically inflamed stomach. Because the mechanism of Aim2 in gastric pathology remained unclear, we screened several gastric immune populations from chronically infected Aim2-/stomachs versus WT stomachs. Previous reports have documented several immune subtypes that increase during chronic gastric inflammation and SPEM (22-28). These include CD11b + Ly6G + myeloid-derived suppressor cells (MDSCs) (22-24), CD11b + Ly6Gmyeloid cells (22), CD4 + and CD8 + T cells (25-27), and B220 + IgM + B cells (28). We therefore screened these populations in our system (Figure 2A). In chronically infected WT stomachs, we observed a significant increase in all these populations relative to uninfected WT stomachs (Figure 2A). However, gastric CD8 + T cells were the only population whose frequency was affe...

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Section: Discussionsupporting

confidence: 92%

Aim2-mediated/IFN-β–independent regulation of gastric metaplastic lesions via CD8+ T cells

El–Zaatari¹,

Bishu²,

Zhang³

et al. 2020

JCI Insight

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“…This study began with the observation that a substantial portion of influenza-specific memory CD8 + T cells in the medLN bearing canonical residency markers expressed Thy1.1 bright , similarly to those in upstream respiratory tissues. We found additional examples in the literature of discrepancies in Thy1.1 staining on cells isolated from NLT versus SLO (Khan et al, 2016;Wein et al, 2019). The biological significance of expressing elevated Thy1.1 requires further investigation, but nevertheless, a Thy1.1 bright phenotype might provide a useful tool for discriminating T RM from i.v.…”

Section: Discussionmentioning

confidence: 81%

Retrograde migration supplies resident memory T cells to lung-draining LN after influenza infection

Stolley

Johnston

Soerens

et al. 2020

Journal of Experimental Medicine

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Numerous observations indicate that resident memory T cells (TRM) undergo unusually rapid attrition within the lung. Here we demonstrate that contraction of lung CD8+ T cell responses after influenza infection is contemporized with egress of CD69+/CD103+ CD8+ T cells to the draining mediastinal LN via the lymphatic vessels, which we term retrograde migration. Cells within the draining LN retained canonical markers of lung TRM, including CD103 and CD69, lacked Ly6C expression (also a feature of lung TRM), maintained granzyme B expression, and did not equilibrate among immunized parabiotic mice. Investigations of bystander infection or removal of the TCR from established memory cells revealed that the induction of the TRM phenotype was dependent on antigen recognition; however, maintenance was independent. Thus, local lung infection induces CD8+ T cells with a TRM phenotype that nevertheless undergo retrograde migration, yet remain durably committed to the residency program within the draining LN, where they provide longer-lived regional memory while chronicling previous upstream antigen experiences.

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“…The rst cluster C0_CD8-CCL5 cells characterised by marker genes Ccl5 50 , Cd3e 51 , Cxcr6 52 and Gzmk 53 , were considered as memory T cells. Most of the top 20 highly expressed genes in the second cluster were various ribosomal proteins, such as Rpl32, Rpl26, Rpl23 and Rpl28.…”

Section: Resultsmentioning

confidence: 99%

Intra-tumoral injection of caerin 1.1 and 1.9 peptides in vaccinated TC-1 tumour bearing mice with PD-1 blockade modulates macrophage heterogeneity and the activation of CD8+ T cells in the tumour microenvironment

Ni¹,

Wu²,

Liu³

et al. 2020

Preprint

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Development of a vaccine formula that alters the tumour-infiltrating lymphocytes to be more immune active against a tumour is key to the improvement of clinical responses to immunotherapy. Here, we demonstrate that, in conjunction with E7 antigen specific immunotherapy, and IL-10 and PD-1 blockade, intra-tumoral administration of caerin 1.1 and 1.9 peptides further improves the tumour microenvironment (TME) when compared with injection of a control peptide. We used single cell transcriptomics and mass spectrometry-based proteomics to quantify changes in cellular activity across different cell types within the TME. We show that the injection of caerin 1.1/1.9 increases immune activating macrophages and NK cells, while reducing immunosuppressive macrophages with M2 phenotype, and increased numbers of activated CD8+ T cells with higher populations of memory and effector-memory CD8+ T subsets. Proteomic profiling demonstrated activation of Stat1 modulated apoptosis and production of nitric oxide. Further, computational integration of the proteome with the single cell transcriptome was consistent with deactivation of immune suppressive B cell function following caerin 1.1 and 1.9 treatment.

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CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways

Cited by 226 publications

References 41 publications

Aim2-mediated/IFN-β–independent regulation of gastric metaplastic lesions via CD8+ T cells

Aim2-mediated/IFN-β–independent regulation of gastric metaplastic lesions via CD8+ T cells

Retrograde migration supplies resident memory T cells to lung-draining LN after influenza infection

Intra-tumoral injection of caerin 1.1 and 1.9 peptides in vaccinated TC-1 tumour bearing mice with PD-1 blockade modulates macrophage heterogeneity and the activation of CD8+ T cells in the tumour microenvironment

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