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Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing.

Lee M, Kiefel H, LaJevic MD, Macauley MS, Kawashima H, O'Hara E, Pan J, Paulson JC, Butcher EC - Nat. Immunol. (2014)

Bottom Line: We performed transcriptomic analyses and identified molecular signatures that distinguish HEVs from capillary endothelium and that define tissue-specific HEV specialization.Capillaries expressed gene programs for vascular development.We also elucidate a carbohydrate-recognition pathway that targets B cells to intestinal lymphoid tissues, defining CD22 as a lectin-homing receptor for mucosal HEVs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

ABSTRACT
Lymphocytes are recruited from blood by high-endothelial venules (HEVs). We performed transcriptomic analyses and identified molecular signatures that distinguish HEVs from capillary endothelium and that define tissue-specific HEV specialization. Capillaries expressed gene programs for vascular development. HEV-expressed genes showed enrichment for genes encoding molecules involved in immunological defense and lymphocyte migration. We identify capillary and HEV markers and candidate mechanisms for regulated recruitment of lymphocytes, including a lymph node HEV-selective transmembrane mucin; transcriptional control of functionally specialized carbohydrate ligands for lymphocyte L-selectin; HEV expression of molecules for transendothelial migration; and metabolic programs for lipid mediators of lymphocyte motility and chemotaxis. We also elucidate a carbohydrate-recognition pathway that targets B cells to intestinal lymphoid tissues, defining CD22 as a lectin-homing receptor for mucosal HEVs.

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Expression of selected cytokines/chemokines, their receptors, integrins, GPCRs, transcription factors, mucin and Ig domain containing adhesion receptors in HEV and CAP of lymphoid tissues. (a) Heatmap of selected gene families as indicated in the figure (EV > 140 in any of the samples). Genes are colored in the heatmap based on log2 normalized expression values as indicated. Blue gene symbols indicate the mean EV for at least one of the cell types is less than 140. Numbers on the right indicate the highest mean EV among the cell types. (b) Expression (EV × 10–3) of genes for selected Ig family, mucin domain, selectin, and other adhesion receptors, and of selected enzymes implicated in phospholipid and oxysterol metabolism. The EV for each biological replicate is plotted with mean and SEM. (c) Representative Immunofluorescence images of PLN cryosections stained with anti-Parm1 (red) and MECA-79 (green). Data are representative of 3 independent experiments. Scale bar is 100 μm. Enlarged insert illustrates HEV surface detection of Parm1 (yellow arrow).
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Figure 4: Expression of selected cytokines/chemokines, their receptors, integrins, GPCRs, transcription factors, mucin and Ig domain containing adhesion receptors in HEV and CAP of lymphoid tissues. (a) Heatmap of selected gene families as indicated in the figure (EV > 140 in any of the samples). Genes are colored in the heatmap based on log2 normalized expression values as indicated. Blue gene symbols indicate the mean EV for at least one of the cell types is less than 140. Numbers on the right indicate the highest mean EV among the cell types. (b) Expression (EV × 10–3) of genes for selected Ig family, mucin domain, selectin, and other adhesion receptors, and of selected enzymes implicated in phospholipid and oxysterol metabolism. The EV for each biological replicate is plotted with mean and SEM. (c) Representative Immunofluorescence images of PLN cryosections stained with anti-Parm1 (red) and MECA-79 (green). Data are representative of 3 independent experiments. Scale bar is 100 μm. Enlarged insert illustrates HEV surface detection of Parm1 (yellow arrow).

Mentions: HEVs as well as CAP expressed genes for receptors for immune cytokines (Fig. 4a). Genes encoding the IL1 receptor IL1r1 and several TNF receptor family members (Tnfrsf9, Tnfrsf11a, Relt, and Eda2r) were preferentially expressed in HEVs, while Fas and Tnfrsf11b were higher in CAP. Tnfrsf1a and Ltbr were uniformly high in both HEVs and CAP. IL3ra, Csf2ra and their common beta chain co-receptor Csf2rb were expressed by CAP and HEVs. IL2rg, the common gamma chain, was highly expressed and somewhat preferentially by HEVs. While HEVs and CAP similarly expressed genes for type 1 interferon (IFN) and IFN-γ receptors, HEVs expressed Ifngr2 more highly than CAP. Transcripts for receptors for IL-27, IL-11, oncostatin M, and leukocyte inhibitory factor (IL27ra, Osmr, Il11ra and Lifr) and their common partner chain Il6st (gp130) were expressed by HEVs; expression of IL27ra and Il6st was HEV selective. Interestingly, CAP but not HECs constitutively expressed transcript for IL-6, which is cytoprotective for ECs14, whereas Il6ra was expressed in both HEV and CAP. Thus HEVs and CAP have both distinct and overlapping receptors for homeostatic and inflammatory cytokines.


Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing.

Lee M, Kiefel H, LaJevic MD, Macauley MS, Kawashima H, O'Hara E, Pan J, Paulson JC, Butcher EC - Nat. Immunol. (2014)

Expression of selected cytokines/chemokines, their receptors, integrins, GPCRs, transcription factors, mucin and Ig domain containing adhesion receptors in HEV and CAP of lymphoid tissues. (a) Heatmap of selected gene families as indicated in the figure (EV > 140 in any of the samples). Genes are colored in the heatmap based on log2 normalized expression values as indicated. Blue gene symbols indicate the mean EV for at least one of the cell types is less than 140. Numbers on the right indicate the highest mean EV among the cell types. (b) Expression (EV × 10–3) of genes for selected Ig family, mucin domain, selectin, and other adhesion receptors, and of selected enzymes implicated in phospholipid and oxysterol metabolism. The EV for each biological replicate is plotted with mean and SEM. (c) Representative Immunofluorescence images of PLN cryosections stained with anti-Parm1 (red) and MECA-79 (green). Data are representative of 3 independent experiments. Scale bar is 100 μm. Enlarged insert illustrates HEV surface detection of Parm1 (yellow arrow).
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Related In: Results  -  Collection

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Figure 4: Expression of selected cytokines/chemokines, their receptors, integrins, GPCRs, transcription factors, mucin and Ig domain containing adhesion receptors in HEV and CAP of lymphoid tissues. (a) Heatmap of selected gene families as indicated in the figure (EV > 140 in any of the samples). Genes are colored in the heatmap based on log2 normalized expression values as indicated. Blue gene symbols indicate the mean EV for at least one of the cell types is less than 140. Numbers on the right indicate the highest mean EV among the cell types. (b) Expression (EV × 10–3) of genes for selected Ig family, mucin domain, selectin, and other adhesion receptors, and of selected enzymes implicated in phospholipid and oxysterol metabolism. The EV for each biological replicate is plotted with mean and SEM. (c) Representative Immunofluorescence images of PLN cryosections stained with anti-Parm1 (red) and MECA-79 (green). Data are representative of 3 independent experiments. Scale bar is 100 μm. Enlarged insert illustrates HEV surface detection of Parm1 (yellow arrow).
Mentions: HEVs as well as CAP expressed genes for receptors for immune cytokines (Fig. 4a). Genes encoding the IL1 receptor IL1r1 and several TNF receptor family members (Tnfrsf9, Tnfrsf11a, Relt, and Eda2r) were preferentially expressed in HEVs, while Fas and Tnfrsf11b were higher in CAP. Tnfrsf1a and Ltbr were uniformly high in both HEVs and CAP. IL3ra, Csf2ra and their common beta chain co-receptor Csf2rb were expressed by CAP and HEVs. IL2rg, the common gamma chain, was highly expressed and somewhat preferentially by HEVs. While HEVs and CAP similarly expressed genes for type 1 interferon (IFN) and IFN-γ receptors, HEVs expressed Ifngr2 more highly than CAP. Transcripts for receptors for IL-27, IL-11, oncostatin M, and leukocyte inhibitory factor (IL27ra, Osmr, Il11ra and Lifr) and their common partner chain Il6st (gp130) were expressed by HEVs; expression of IL27ra and Il6st was HEV selective. Interestingly, CAP but not HECs constitutively expressed transcript for IL-6, which is cytoprotective for ECs14, whereas Il6ra was expressed in both HEV and CAP. Thus HEVs and CAP have both distinct and overlapping receptors for homeostatic and inflammatory cytokines.

Bottom Line: We performed transcriptomic analyses and identified molecular signatures that distinguish HEVs from capillary endothelium and that define tissue-specific HEV specialization.Capillaries expressed gene programs for vascular development.We also elucidate a carbohydrate-recognition pathway that targets B cells to intestinal lymphoid tissues, defining CD22 as a lectin-homing receptor for mucosal HEVs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

ABSTRACT
Lymphocytes are recruited from blood by high-endothelial venules (HEVs). We performed transcriptomic analyses and identified molecular signatures that distinguish HEVs from capillary endothelium and that define tissue-specific HEV specialization. Capillaries expressed gene programs for vascular development. HEV-expressed genes showed enrichment for genes encoding molecules involved in immunological defense and lymphocyte migration. We identify capillary and HEV markers and candidate mechanisms for regulated recruitment of lymphocytes, including a lymph node HEV-selective transmembrane mucin; transcriptional control of functionally specialized carbohydrate ligands for lymphocyte L-selectin; HEV expression of molecules for transendothelial migration; and metabolic programs for lipid mediators of lymphocyte motility and chemotaxis. We also elucidate a carbohydrate-recognition pathway that targets B cells to intestinal lymphoid tissues, defining CD22 as a lectin-homing receptor for mucosal HEVs.

Show MeSH
Related in: MedlinePlus