Efficient Recruitment of Lymphocytes in Inflamed Brain Venules Requires Expression of Cutaneous Lymphocyte Antigen and Fucosyltransferase-VII

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.

Identification of cutaneous lymphocyte-associated antigen as sialyl 6-sulfo Lewis X, a selectin ligand expressed on a subset of skin-homing helper memory T cells

“…It has recently been reported that Fuc-T VII participates in the synthesis of CLA in the murine system. 49 Our results suggest that this enzyme is involved in the synthesis of sialyl 6-sulfo Le x in human skin-homing cells. Helper memory T cells and NK cells exhibit constitutive activation of HEC-GlcNAc6ST and Fuc-T VII compared with other human peripheral lymphocyte subpopulations.…”

Sodium Benzoate, a Food Additive and a Metabolite of Cinnamon, Modifies T Cells at Multiple Steps and Inhibits Adoptive Transfer of Experimental Allergic Encephalomyelitis

“…These results suggest that NaB prevents adhesion and transendothelial migration of encephalitogenic lymphocytes by suppressing the expression of integrins and adhesion molecules. Similarly, the role of E-and P-selectins in the extravasation of T lymphocytes into the CNS is also evident when complete inhibition of rolling and arrest of Th1 cells in inflamed brain was observed with anti-E-and P-selectin Abs (23). Interestingly, NaB was also found to inhibit the expression of E-and P-selectins in the cerebellum as well as in the spinal cord of EAE mice.…”

Immune cell entry into the central nervous system: Involvement of adhesion molecules and chemokines

“…These approaches have even demonstrated that different molecular mechanisms guide CD8 + T cells and CD4 + T cells into the CNS, as CD8 + T cells from MS patients were shown to preferentially roll via P-selectin glycoprotein ligand (PSGL-1), whereas CD4 + T cells rolled via α4-integrin [11]. In addition, these studies showed that specifically the carbohydrate modification of PSGL-1 known as the cutaneous lymphocyte antigen (CLA) is required for leukocyte rolling in superficial brain vessels [12]. During EAE, both, α4-integrin and PSGL-1 were shown to mediate the rolling of endogenous leukocytes in inflamed superficial brain vessels [8].…”