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Fuc-TVII is required for T helper 1 and T cytotoxic 1 lymphocyte selectin ligand expression and recruitment in inflammation, and together with Fuc-TIV regulates naive T cell trafficking to lymph nodes.

Smithson G, Rogers CE, Smith PL, Scheidegger EP, Petryniak B, Myers JT, Kim DS, Homeister JW, Lowe JB - J. Exp. Med. (2001)

Bottom Line: These defects are not accounted for by alterations in the number or function of epidermal Langerhans cells required for cutaneous antigen processing and presentation.Fuc-TVII deficiency also deletes expression of E- and P-selectin ligands by Th1 and T cytotoxic 1 (Tc1) lymphocytes, annuls T cell trafficking to inflamed cutaneous sites in vivo, and thereby controls an essential component of the efferent phase of the cutaneous immune response.These observations indicate that collaborative contributions of Fuc-TIV and Fuc-TVII to L-selectin ligand synthesis, and to lymphocyte recruitment, are requisite components of the primary cellular immune response, and assign an essential role to Fuc-TVII in control of E- and P-selectin ligand expression by Th1 and Tc1 lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
To determine how the alpha(1,3)fucosyltransferases Fuc-TIV and Fuc-TVII, and the selectin ligands they control may contribute to the adaptive immune response, contact hypersensitivity (CHS) was characterized in mice deficient in either or both enzymes. We find a substantial CHS deficiency in Fuc-TVII(-/-) mice, and a complete deficiency in Fuc-TIV(-/-)/Fuc-TVII(-/-) mice. These defects are not accounted for by alterations in the number or function of epidermal Langerhans cells required for cutaneous antigen processing and presentation. By contrast, defective CHS in Fuc-TVII(-/-) mice or Fuc-TIV(-/-)/Fuc-TVII(-/-) mice is attributed in part to prominent, or nearly complete deficiencies, respectively, in the complement of naive T lymphocytes available in lymph nodes for antigen-dependent activation, expansion, differentiation, and dissemination. Fuc-TVII deficiency also deletes expression of E- and P-selectin ligands by Th1 and T cytotoxic 1 (Tc1) lymphocytes, annuls T cell trafficking to inflamed cutaneous sites in vivo, and thereby controls an essential component of the efferent phase of the cutaneous immune response. These observations indicate that collaborative contributions of Fuc-TIV and Fuc-TVII to L-selectin ligand synthesis, and to lymphocyte recruitment, are requisite components of the primary cellular immune response, and assign an essential role to Fuc-TVII in control of E- and P-selectin ligand expression by Th1 and Tc1 lymphocytes.

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Selectin ligand expression by Th1 cells in WT and Fuc-T–deficient mice. CD4+ T cells were isolated from mesenteric nodes and cultured in vitro under Th1 polarization conditions (Materials and Methods). Cells were then subjected to flow cytometry analysis to confirm Th1 polarization by assessing expression of intracellular IFN-γ and IL-4 (A), or to assess selectin ligand expression using P-selectin-IgM or E-selectin-IgM chimeras (B). Divalent calcium dependence observed for binding of the P-selectin-IgM chimera (B, bottom) was also observed for the E-selectin-IgM chimera (data not shown). Data shown are representative of two or more independent experiments. Vertical and horizontal lines in the histograms define the fluorescence intensities below which 99% of the cells fall when analyzed using a nonbinding isotype control for AntiCD3, or observed with either selectin chimera used in the presence of 5 mM EDTA.
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Figure 7: Selectin ligand expression by Th1 cells in WT and Fuc-T–deficient mice. CD4+ T cells were isolated from mesenteric nodes and cultured in vitro under Th1 polarization conditions (Materials and Methods). Cells were then subjected to flow cytometry analysis to confirm Th1 polarization by assessing expression of intracellular IFN-γ and IL-4 (A), or to assess selectin ligand expression using P-selectin-IgM or E-selectin-IgM chimeras (B). Divalent calcium dependence observed for binding of the P-selectin-IgM chimera (B, bottom) was also observed for the E-selectin-IgM chimera (data not shown). Data shown are representative of two or more independent experiments. Vertical and horizontal lines in the histograms define the fluorescence intensities below which 99% of the cells fall when analyzed using a nonbinding isotype control for AntiCD3, or observed with either selectin chimera used in the presence of 5 mM EDTA.

Mentions: Th1 and Tc1 lymphocytes, defined in part by their characteristic IFN-γ expression properties 35, are generated in draining PLNs after antigen sensitization, traffic via the circulation to the skin, and contribute to the cutaneous inflammatory response during elicitation/challenge 353637. Th1 and Tc1 progenitors most likely derive from naive T lymphocytes recruited to PLNs primarily by L-selectin–dependent mechanisms (discussed in reference 11). As Fuc-TIV and Fuc-TVII contribute to L-selectin–dependent lymphocyte recruitment 68, we sought to determine if their deficiency altered the accumulation or generation of such IFN-γ–expressing lymphocytes in a way that contributes to defective CHS in the Fuc-T–deficient mice. The numbers of these cells were equivalently low in the PLNs of nonsensitized WT and all Fuc-T–deficient strains (Fig. 6). Significant increases in these cells are observed in WT and Fuc-TIV−/− mice after DNFB sensitization (Fig. 6A and Fig. B). By contrast, in Fuc-TVII−/− mice and the doubly deficient mice, sensitization did not significantly increase the number of such IFN-γ–positive CD4+ or CD8+ lymphocytes. Graded, genotype-specific decrements in the absolute number of these cells recovered from the PLNs of the sensitized mice were also observed, and are most apparent and significant in the doubly deficient mice (Fig. 6). These decrements imply that Fuc-TIV and Fuc-TVII contribute independently to hapten-dependent accumulation of Th1 and Tc1 cells in vivo. To exclude the possibility that the Fuc-Ts also or instead contribute to properties intrinsic to Th1 and Tc1 precursors that allow them to proceed through the polarization process, WT- and Fuc-T–deficient naive T cells were characterized for their ability to differentiate into Th1 or Tc1 cells in vitro. These experiments show that naive CD4+ or CD8+ T cells isolated from each Fuc-T strain respond to cytokine polarization by differentiating into cells with a Th1 (IFN-γ+IL-4−) or Tc1 (IFN-γ+IL-4−) phenotype (Fig. 7 A and 8 A). These observations imply that defective generation of Th1 and Tc1 cells in Fuc-TVII−/− and Fuc-TIV−/−/VII−/− mice in response to haptenic sensitization (Fig. 6) is due to a deficiency in the number of naive Th1 cell and Tc1 cell progenitors available for cytokine-dependent polarization, and not to an intrinsic differentiation defect. In vitro polarization towards the Th2 (CD4+IFN-γ−IL-4+) and Tc2 (CD8+IFN-γ−IL-4+) phenotypes is also retained in the absence of Fuc-TIV and/or Fuc-TVII (data not shown), indicating that neither enzyme is required for these alternative differentiation pathways.


Fuc-TVII is required for T helper 1 and T cytotoxic 1 lymphocyte selectin ligand expression and recruitment in inflammation, and together with Fuc-TIV regulates naive T cell trafficking to lymph nodes.

Smithson G, Rogers CE, Smith PL, Scheidegger EP, Petryniak B, Myers JT, Kim DS, Homeister JW, Lowe JB - J. Exp. Med. (2001)

Selectin ligand expression by Th1 cells in WT and Fuc-T–deficient mice. CD4+ T cells were isolated from mesenteric nodes and cultured in vitro under Th1 polarization conditions (Materials and Methods). Cells were then subjected to flow cytometry analysis to confirm Th1 polarization by assessing expression of intracellular IFN-γ and IL-4 (A), or to assess selectin ligand expression using P-selectin-IgM or E-selectin-IgM chimeras (B). Divalent calcium dependence observed for binding of the P-selectin-IgM chimera (B, bottom) was also observed for the E-selectin-IgM chimera (data not shown). Data shown are representative of two or more independent experiments. Vertical and horizontal lines in the histograms define the fluorescence intensities below which 99% of the cells fall when analyzed using a nonbinding isotype control for AntiCD3, or observed with either selectin chimera used in the presence of 5 mM EDTA.
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Related In: Results  -  Collection

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Figure 7: Selectin ligand expression by Th1 cells in WT and Fuc-T–deficient mice. CD4+ T cells were isolated from mesenteric nodes and cultured in vitro under Th1 polarization conditions (Materials and Methods). Cells were then subjected to flow cytometry analysis to confirm Th1 polarization by assessing expression of intracellular IFN-γ and IL-4 (A), or to assess selectin ligand expression using P-selectin-IgM or E-selectin-IgM chimeras (B). Divalent calcium dependence observed for binding of the P-selectin-IgM chimera (B, bottom) was also observed for the E-selectin-IgM chimera (data not shown). Data shown are representative of two or more independent experiments. Vertical and horizontal lines in the histograms define the fluorescence intensities below which 99% of the cells fall when analyzed using a nonbinding isotype control for AntiCD3, or observed with either selectin chimera used in the presence of 5 mM EDTA.
Mentions: Th1 and Tc1 lymphocytes, defined in part by their characteristic IFN-γ expression properties 35, are generated in draining PLNs after antigen sensitization, traffic via the circulation to the skin, and contribute to the cutaneous inflammatory response during elicitation/challenge 353637. Th1 and Tc1 progenitors most likely derive from naive T lymphocytes recruited to PLNs primarily by L-selectin–dependent mechanisms (discussed in reference 11). As Fuc-TIV and Fuc-TVII contribute to L-selectin–dependent lymphocyte recruitment 68, we sought to determine if their deficiency altered the accumulation or generation of such IFN-γ–expressing lymphocytes in a way that contributes to defective CHS in the Fuc-T–deficient mice. The numbers of these cells were equivalently low in the PLNs of nonsensitized WT and all Fuc-T–deficient strains (Fig. 6). Significant increases in these cells are observed in WT and Fuc-TIV−/− mice after DNFB sensitization (Fig. 6A and Fig. B). By contrast, in Fuc-TVII−/− mice and the doubly deficient mice, sensitization did not significantly increase the number of such IFN-γ–positive CD4+ or CD8+ lymphocytes. Graded, genotype-specific decrements in the absolute number of these cells recovered from the PLNs of the sensitized mice were also observed, and are most apparent and significant in the doubly deficient mice (Fig. 6). These decrements imply that Fuc-TIV and Fuc-TVII contribute independently to hapten-dependent accumulation of Th1 and Tc1 cells in vivo. To exclude the possibility that the Fuc-Ts also or instead contribute to properties intrinsic to Th1 and Tc1 precursors that allow them to proceed through the polarization process, WT- and Fuc-T–deficient naive T cells were characterized for their ability to differentiate into Th1 or Tc1 cells in vitro. These experiments show that naive CD4+ or CD8+ T cells isolated from each Fuc-T strain respond to cytokine polarization by differentiating into cells with a Th1 (IFN-γ+IL-4−) or Tc1 (IFN-γ+IL-4−) phenotype (Fig. 7 A and 8 A). These observations imply that defective generation of Th1 and Tc1 cells in Fuc-TVII−/− and Fuc-TIV−/−/VII−/− mice in response to haptenic sensitization (Fig. 6) is due to a deficiency in the number of naive Th1 cell and Tc1 cell progenitors available for cytokine-dependent polarization, and not to an intrinsic differentiation defect. In vitro polarization towards the Th2 (CD4+IFN-γ−IL-4+) and Tc2 (CD8+IFN-γ−IL-4+) phenotypes is also retained in the absence of Fuc-TIV and/or Fuc-TVII (data not shown), indicating that neither enzyme is required for these alternative differentiation pathways.

Bottom Line: These defects are not accounted for by alterations in the number or function of epidermal Langerhans cells required for cutaneous antigen processing and presentation.Fuc-TVII deficiency also deletes expression of E- and P-selectin ligands by Th1 and T cytotoxic 1 (Tc1) lymphocytes, annuls T cell trafficking to inflamed cutaneous sites in vivo, and thereby controls an essential component of the efferent phase of the cutaneous immune response.These observations indicate that collaborative contributions of Fuc-TIV and Fuc-TVII to L-selectin ligand synthesis, and to lymphocyte recruitment, are requisite components of the primary cellular immune response, and assign an essential role to Fuc-TVII in control of E- and P-selectin ligand expression by Th1 and Tc1 lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
To determine how the alpha(1,3)fucosyltransferases Fuc-TIV and Fuc-TVII, and the selectin ligands they control may contribute to the adaptive immune response, contact hypersensitivity (CHS) was characterized in mice deficient in either or both enzymes. We find a substantial CHS deficiency in Fuc-TVII(-/-) mice, and a complete deficiency in Fuc-TIV(-/-)/Fuc-TVII(-/-) mice. These defects are not accounted for by alterations in the number or function of epidermal Langerhans cells required for cutaneous antigen processing and presentation. By contrast, defective CHS in Fuc-TVII(-/-) mice or Fuc-TIV(-/-)/Fuc-TVII(-/-) mice is attributed in part to prominent, or nearly complete deficiencies, respectively, in the complement of naive T lymphocytes available in lymph nodes for antigen-dependent activation, expansion, differentiation, and dissemination. Fuc-TVII deficiency also deletes expression of E- and P-selectin ligands by Th1 and T cytotoxic 1 (Tc1) lymphocytes, annuls T cell trafficking to inflamed cutaneous sites in vivo, and thereby controls an essential component of the efferent phase of the cutaneous immune response. These observations indicate that collaborative contributions of Fuc-TIV and Fuc-TVII to L-selectin ligand synthesis, and to lymphocyte recruitment, are requisite components of the primary cellular immune response, and assign an essential role to Fuc-TVII in control of E- and P-selectin ligand expression by Th1 and Tc1 lymphocytes.

Show MeSH
Related in: MedlinePlus