title: Role of IL-16 in CD4+ T cell-mediated regulation of relapsing multiple sclerosis.
abstract: In an important article published in Nature Medicine, Liu and colleagues described a novel CD4(+) FoxA1(+) regulatory T (Treg) cell population as distinct regulators of relapsing-remitting multiple sclerosis (RRMS) and experimental autoimmune encephalomyelitis (EAE). CD4(+) FoxA1(+) Treg cells appear as key regulators of responsiveness to therapy with interferon beta (IFN-β) in RRMS patients. Data indicate that CD4(+)FoxA1(+) FOXP3(-) Treg cells develop within the central nervous system (CNS), and a potential of cerebellar granule neurons (CGN) in generation of CD4(+)FoxA1(+)PD-L1(hi)FOXP3(-) Treg cells from encephalitogenic CD4(+) T cells. A CD4 co-receptor specific ligand, IL-16, governs trafficking and biological properties of CD4(+) T cells irrespective of their activation state. Functions of IL-16, relevant to Treg cells, include expansion of CD4(+)CD25(+) T cells in long-term cultures with IL-2, de novo induction of FOXP-3 and migration of FOXP-3(+) T cells. IL-16 is highly conserved across species including human and mouse. CGN and neurons in hippocampus contain neuronal-IL-16 (NIL-16), splice variant of immune IL-16, and express CD4 molecule. In a CD4-dependent manner, IL-16 supports cultured CGN survival. Concomitant studies of RRMS lesions and corresponding MOG35-55-induced relapsing EAE in (B6 × JL)F1 (H-2(b/s)) mice discovered similar roles of IL-16 in regulation of relapsing disease. In RRMS and EAE relapse, peak levels of IL-16 and active caspase-3 correlated with CD4(+) T cell infiltration and levels of T-bet, Stat-1(Tyr(701)), and phosphorylated neurofilaments of axonal cytoskeleton [NF (M + H) P], suggesting a role of locally produced IL-16 in regulation of CD4(+) Th1 inflammation and axonal damage, respectively. IL-16 was abundantly present in CD4(+) T cells, followed by CD20(+) B, CD8(+) T, CD83(+) dendritic cells, and Mac-1(+) microglia. Apart from lesions, bioactive IL-16 was located in normal-appearing white matter (NAWM) and normal-appearing grey matter (NAGM) in RRMS brain and spinal cord. A cytokine IL-16 emerges as an important regulator of relapsing MS and EAE. Better understanding of immune cell-neuron interactions mediated by IL-16 will foster development of more specific CD4(+) T cell subset-targeted therapies to prevent or ameliorate progression of neuroinflammation and axonal and neuronal damage. Translational studies necessitate corresponding EAE models.
authors.affiliation: Department of Immunology and Microbiology, Wayne State University, 540 East Canfield Av., Detroit, MI, USA. Skundric@wayne.edu.
authors.forename: Dusanka S
authors.initials: DS
authors.lastname: Skundric
authors.affiliation: Pulmonary Center Boston University, 715 Albany Street, Boston, MA, USA. bcruiksh@bu.edu.
authors.forename: William W
authors.initials: WW
authors.lastname: Cruikshank
authors.affiliation: Clinic of Neurology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Subotica 6, Belgrade, Serbia. jelena60@EUnet.rs.
authors.forename: Jelena
authors.initials: J
authors.lastname: Drulovic
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D006801:Humans; D019410:Interleukin-16 / Q000378:metabolism*; D051379:Mice; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity
chemical_list: D019410:Interleukin-16; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55)