Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII

Laura Piccio, Barbara Rossi, Lucia Colantonio, Roland Grenningloh, Andrea Gho, Linda Ottoboni, Jonathon W. Homeister, Elio Scarpini, Marianna Martinello, Carlo Laudanna, Daniele D'Ambrosio, John B. Lowe, Gabriela Constantin

Research output: Contribution to journalArticle

Abstract

Lymphocyte migration into the brain represents a critical event in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the mechanisms controlling the recruitment of lymphocytes to the CNS via inflamed brain venules are poorly understood, and therapeutic approaches to inhibit this process are consequently few. In this study, we demonstrate for the first time that human and murine Th1 lymphocytes preferentially adhere to murine inflamed brain venules in an experimental model that mimics early inflammation during EAE. A virtually complete inhibition of rolling and arrest of Th1 cells in inflamed brain venules was observed with a blocking anti-P-selectin glycoprotein ligand 1 Ab and anti-E- and P-selectin Abs. Th1 lymphocytes produced from fucosyltransferase (FucT)-IV-/- mice efficiently tethered and rolled, whereas in contrast, primary adhesion of Th1 lymphocytes obtained from FucT-VII-/- or Fuc-VII -/-FucT-IV-/- mice was drastically reduced, indicating that FucT-VII is critical for the recruitment of Th1 cells in inflamed brain microcirculation. Importantly, we show that Abs directed against cutaneous lymphocyte Ag (CLA), a FucT-VII-dependent carbohydrate modification of P-selectin glycoprotein ligand 1, blocked rolling of Th1 cells. By exploiting a system that allowed us to obtain Th1 and Th2 cells with skin- vs gut-homing (CLA+ vs integrin β7+) phenotypes, we observed that induced expression of CLA on Th cells determined a striking increase of rolling efficiency in inflamed brain venules. These observations allow us to conclude that efficient recruitment of activated lymphocytes to the brain in the contexts mimicking EAE is controlled by FucT-VII and its cognate cell surface Ag CLA.

Original languageEnglish
Pages (from-to)5805-5813
Number of pages9
JournalJournal of Immunology
Volume174
Issue number9
Publication statusPublished - May 1 2005

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Fucosyltransferases
Venules
Lymphocytes
Antigens
Skin
Brain
Th1 Cells
Autoimmune Experimental Encephalomyelitis
Th2 Cells
P-Selectin
E-Selectin
Microcirculation
Integrins
Multiple Sclerosis
Theoretical Models
Animal Models
Carbohydrates

ASJC Scopus subject areas

  • Immunology

Cite this

Piccio, L., Rossi, B., Colantonio, L., Grenningloh, R., Gho, A., Ottoboni, L., ... Constantin, G. (2005). Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII. Journal of Immunology, 174(9), 5805-5813.

Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII. / Piccio, Laura; Rossi, Barbara; Colantonio, Lucia; Grenningloh, Roland; Gho, Andrea; Ottoboni, Linda; Homeister, Jonathon W.; Scarpini, Elio; Martinello, Marianna; Laudanna, Carlo; D'Ambrosio, Daniele; Lowe, John B.; Constantin, Gabriela.

In: Journal of Immunology, Vol. 174, No. 9, 01.05.2005, p. 5805-5813.

Research output: Contribution to journalArticle

Piccio, L, Rossi, B, Colantonio, L, Grenningloh, R, Gho, A, Ottoboni, L, Homeister, JW, Scarpini, E, Martinello, M, Laudanna, C, D'Ambrosio, D, Lowe, JB & Constantin, G 2005, 'Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII', Journal of Immunology, vol. 174, no. 9, pp. 5805-5813.
Piccio, Laura ; Rossi, Barbara ; Colantonio, Lucia ; Grenningloh, Roland ; Gho, Andrea ; Ottoboni, Linda ; Homeister, Jonathon W. ; Scarpini, Elio ; Martinello, Marianna ; Laudanna, Carlo ; D'Ambrosio, Daniele ; Lowe, John B. ; Constantin, Gabriela. / Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII. In: Journal of Immunology. 2005 ; Vol. 174, No. 9. pp. 5805-5813.
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abstract = "Lymphocyte migration into the brain represents a critical event in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the mechanisms controlling the recruitment of lymphocytes to the CNS via inflamed brain venules are poorly understood, and therapeutic approaches to inhibit this process are consequently few. In this study, we demonstrate for the first time that human and murine Th1 lymphocytes preferentially adhere to murine inflamed brain venules in an experimental model that mimics early inflammation during EAE. A virtually complete inhibition of rolling and arrest of Th1 cells in inflamed brain venules was observed with a blocking anti-P-selectin glycoprotein ligand 1 Ab and anti-E- and P-selectin Abs. Th1 lymphocytes produced from fucosyltransferase (FucT)-IV-/- mice efficiently tethered and rolled, whereas in contrast, primary adhesion of Th1 lymphocytes obtained from FucT-VII-/- or Fuc-VII -/-FucT-IV-/- mice was drastically reduced, indicating that FucT-VII is critical for the recruitment of Th1 cells in inflamed brain microcirculation. Importantly, we show that Abs directed against cutaneous lymphocyte Ag (CLA), a FucT-VII-dependent carbohydrate modification of P-selectin glycoprotein ligand 1, blocked rolling of Th1 cells. By exploiting a system that allowed us to obtain Th1 and Th2 cells with skin- vs gut-homing (CLA+ vs integrin β7+) phenotypes, we observed that induced expression of CLA on Th cells determined a striking increase of rolling efficiency in inflamed brain venules. These observations allow us to conclude that efficient recruitment of activated lymphocytes to the brain in the contexts mimicking EAE is controlled by FucT-VII and its cognate cell surface Ag CLA.",
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AU - Rossi, Barbara

AU - Colantonio, Lucia

AU - Grenningloh, Roland

AU - Gho, Andrea

AU - Ottoboni, Linda

AU - Homeister, Jonathon W.

AU - Scarpini, Elio

AU - Martinello, Marianna

AU - Laudanna, Carlo

AU - D'Ambrosio, Daniele

AU - Lowe, John B.

AU - Constantin, Gabriela

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AB - Lymphocyte migration into the brain represents a critical event in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the mechanisms controlling the recruitment of lymphocytes to the CNS via inflamed brain venules are poorly understood, and therapeutic approaches to inhibit this process are consequently few. In this study, we demonstrate for the first time that human and murine Th1 lymphocytes preferentially adhere to murine inflamed brain venules in an experimental model that mimics early inflammation during EAE. A virtually complete inhibition of rolling and arrest of Th1 cells in inflamed brain venules was observed with a blocking anti-P-selectin glycoprotein ligand 1 Ab and anti-E- and P-selectin Abs. Th1 lymphocytes produced from fucosyltransferase (FucT)-IV-/- mice efficiently tethered and rolled, whereas in contrast, primary adhesion of Th1 lymphocytes obtained from FucT-VII-/- or Fuc-VII -/-FucT-IV-/- mice was drastically reduced, indicating that FucT-VII is critical for the recruitment of Th1 cells in inflamed brain microcirculation. Importantly, we show that Abs directed against cutaneous lymphocyte Ag (CLA), a FucT-VII-dependent carbohydrate modification of P-selectin glycoprotein ligand 1, blocked rolling of Th1 cells. By exploiting a system that allowed us to obtain Th1 and Th2 cells with skin- vs gut-homing (CLA+ vs integrin β7+) phenotypes, we observed that induced expression of CLA on Th cells determined a striking increase of rolling efficiency in inflamed brain venules. These observations allow us to conclude that efficient recruitment of activated lymphocytes to the brain in the contexts mimicking EAE is controlled by FucT-VII and its cognate cell surface Ag CLA.

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