Specific central nervous system recruitment of HLA‐G⁺ regulatory T cells in multiple sclerosis

Abstract

Objective: We have recently described a novel population of natural regulatory T cells (T reg ) that are characterized by the expression of HLA-G and may be found at sites of tissue inflammation (HLA-G pos T reg ). Here we studied the role of these cells in multiple sclerosis (MS), a prototypic autoimmune inflammatory disorder of the central nervous system (CNS). Methods: Sixty-four patients with different types of MS, 9 patients with other neurological diseases, and 20 healthy donors were included in this study. Inflamed brain lesions from 5 additional untreated MS patients were examined. HLA-G pos T reg were analyzed in the cerebrospinal fluid (CSF) by flow cytometry and in inflammatory demyelinating lesions of MS brain specimens by immunohistochemistry. Functional capacity was accessed and transmigration was determined using an in vitro model of the human blood-brain barrier (BBB). Results: HLA-G pos T reg were found enriched in the inflamed CSF of MS patients and in inflammatory demyelinating lesions of MS brain specimens. HLA-G pos T reg showed a strong propensity to transmigrate across BBB, which was vigorously driven by inflammatory chemokines, and associated with a gain of suppressive capacity upon transmigration. CSF-derived HLA-G pos T reg of MS patients represented a population of activated central memory activated T cells with an upregulated expression of inflammatory chemokine receptors and exhibiting full suppressive capacity. Unlike natural FoxP3-expressing T reg , HLA-G pos T reg derived from peripheral blood were functionally unimpaired in MS. Interpretation: In MS, HLA-G pos T reg may serve to control potentially destructive immune responses directly at the sites of CNS inflammation and to counterbalance inflammation once specifically recruited to the CNS.

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

“…Under conditions of experimental autoimmune neuroinflammation as in EAE, Treg accumulate in the murine CNS [4,10], most notably in the remission phases [11], counterbalancing encephalitogenic CNS responses. As mentioned above, data on the presence and function of Treg in the human CNS are sparse [12][13][14]18]. To translate our findings into human pathophysiology, we used an in vitro model of the human BBB to mimic lymphocyte diapedesis in vivo.…”

“…To determine whether human Treg feature similar characteristics in transendothelial migration as their murine counterparts, we used a well-established in vitro model of the human BBB [18]. Primary human brain microvascular endothelial cells (HBMEC) cultured on transwell membranes were used for these experiments.…”

“…Transendothelial migration experiments were performed as described previously [18]. In brief, 3.0-mm pore polyester membrane transwell inserts (Corning) were coated with 100 mg/mL fibronectin and 400 mg/ mL collagen type IV (Sigma-Aldrich) for 30-60 min before 1.5 Â 10 5 HBMEC were added.…”

“…As mentioned above, data on the presence and function of Treg in the human CNS are sparse [12][13][14]18]. To translate our findings into human pathophysiology, we used an in vitro model of the human BBB to mimic lymphocyte diapedesis in vivo.…”

Distinctive Immunological Functions of HLA-G

“…They represent a small subset of peripheral blood cells in healthy individuals, but are increased at sites of inflammation, such as in the central nervous system of patients with neuro-inflammatory disorders and in muscle tissue in patients with idiopathic myositis (Feger et al, 2007;Huang et al, 2009a;Wiendl et al, 2005). CD4 + HLA-G1 + T cells represent a population of naturally occurring Treg cells distinct from nTreg cells, since they lack CD25 and FOXP3 expression.…”