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

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-l1hifoxp3- 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 × sjl)f1 (h-2b/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. © skundric et al.; licensee biomed central.