CD4+NKG2D+ T cells exhibit enhanced migratory and encephalitogenic properties in neuroinflammation

PLoS One. 2013 Nov 25;8(11):e81455. doi: 10.1371/journal.pone.0081455. eCollection 2013.

Abstract

Migration of encephalitogenic CD4(+) T lymphocytes across the blood-brain barrier is an essential step in the pathogenesis of multiple sclerosis (MS). We here demonstrate that expression of the co-stimulatory receptor NKG2D defines a subpopulation of CD4(+) T cells with elevated levels of markers for migration, activation, and cytolytic capacity especially when derived from MS patients. Furthermore, CD4(+)NKG2D(+) cells produce high levels of proinflammatory IFN-γ and IL-17 upon stimulation. NKG2D promotes the capacity of CD4(+)NKG2D(+) cells to migrate across endothelial cells in an in vitro model of the blood-brain barrier. CD4(+)NKG2D(+) T cells are enriched in the cerebrospinal fluid of MS patients, and a significant number of CD4(+) T cells in MS lesions coexpress NKG2D. We further elucidated the role of CD4(+)NKG2D(+) T cells in the mouse system. NKG2D blockade restricted central nervous system migration of T lymphocytes in vivo, leading to a significant decrease in the clinical and pathologic severity of experimental autoimmune encephalomyelitis, an animal model of MS. Blockade of NKG2D reduced killing of cultivated mouse oligodendrocytes by activated CD4(+) T cells. Taken together, we identify CD4(+)NKG2D(+) cells as a subpopulation of T helper cells with enhanced migratory, encephalitogenic and cytotoxic properties involved in inflammatory CNS lesion development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood-Brain Barrier
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology
  • Chemotaxis, Leukocyte*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Humans
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • NK Cell Lectin-Like Receptor Subfamily K / immunology*
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Signal Transduction

Substances

  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K

Grant support

This work was supported by the Transregio centre grant SFB “Multiple Sclerosis” (B1 to NS and HW; B5 to SGM), by the German Ministry for Research and Education (BMBF, UNDERSTANDMS, belonging to the “German Competence Network of MS”, to HW and MP), by Interdisciplinary Center for Clinical Research (IZKF) Münster (SEED 03/12, to SB, KuT3/006/11 to TK and Meu3/010/12 to SGM) and by materials and a project grant by Novo Nordisk, Copenhagen, Denmark (to HW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.