Role of IL-16 in CD4+ T cell-mediated regulation of relapsing multiple sclerosis

Journal of Neuroinflammation

Jelena Drulovic²  William W Cruikshank³  Dusanka S Skundric¹ 

[1] Department of Immunology and Microbiology, Wayne State University, 540 East Canfield Av., Detroit, MI, USA;Clinic of Neurology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Subotica 6, Belgrade, Serbia;Pulmonary Center Boston University, 715 Albany Street, Boston, MA, USA

关键词: Therapy;    Translational;    EAE;    MOG;    FoxA1;    IFN-β;    CD4+ T cells;    Cerebellum;    Multiple sclerosis;    IL-16;   

Others  :  1227090
DOI  :  10.1186/s12974-015-0292-x

 received in 2014-12-30, accepted in 2015-03-31,  发布年份 2015

【 摘 要 】

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^hiFOXP3⁻ 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 MOG_35–55-induced relapsing EAE in (B6 × SJL)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(Tyr⁷⁰¹), 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.

【 授权许可】

   
2015 Skundric et al.; licensee BioMed Central.

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