NKG2 Receptors Acquired by Activated Human CD4 T Cells Are Involved in Oligodendrocyte Destruction in the Context of MS (P07.086)

Abstract

Objective: To characterize novel mechanisms by which CD4 T cells can injure human oligodendrocytes, and identify these cells in patients with Multiple Sclerosis (MS). Background Destruction of oligodendrocytes is a fundamental hallmark of MS. Although CD4 T cells are considered important contributors to this immunopathology, the mechanisms involved are not completely resolved. In recent years, CD4 T cells that acquire NK-associated markers have been implicated in tissue destruction in other immunopathologies such as Crohns Disease. We investigated whether cytotoxic NKG2+ CD4 T cells were detected in MS patients and whether human adult oligodendrocytes express the recognized ligands. We studied whether these receptors were involved in the immune-mediated injury of oligodendrocytes. Design/Methods: Proportions of NKG2D/C+ CD4 T cells in the blood of MS patients versus healthy donors were analyzed using flow cytometry (FACS). Peripheral blood mononuclear cells (PBMCs) from human donors are activated with the lectin phytohemagglutinin (PHA) and stained for NKG2C, NKG2D, CD4. CD4 T cells isolated from these cultures are incubated with primary cultures of human adult oligodendrocytes, and then analyzed by FACS for effector functions. Immunohistochemistry was done on post-mortem CNS sections of MS patients. Results: Our studies show an increased proportion of cytotoxic NKG2D/C+ CD4 T cells in the blood of MS patients. These CD4 T cells expressed elevated levels of lytic enzymes. We have previously shown that inflamed human oligodendrocytes upregulate NKG2D ligands; we now show that they can also express NKG2C ligand (HLA-E) upon inflammatory conditions mimicking MS lesions. Our functional results show that blocking NKG2C and NKG2D on PHA-activated CD4 T cells decreases their cytotoxicity towards the oligodendrocytes. Our in situ studies show that these cells are detected in post-mortem CNS sections of MS patients. Conclusions: Our results demonstrate that activated human CD4 T cells can mediate injury to oligodendrocytes through acquired cytotoxic NK-associated receptors. Supported by: Multiple Sclerosis Society of Canada (MSSOC). Disclosure: Dr. Zaguia has nothing to disclose. Dr. Antel has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Biogen Idec, Novartis, Serono, Inc., Genzyme Corporation, Teva Neuroscience, and GlaxoSmithKline. Dr. Antel has received personal compensation in an editorial capacity for Multiple Sclerosis. Dr. Antel has received research support from Novartis. Dr. Saikali has nothing to disclose. Dr. Arbour has nothing to disclose.