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-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.
Highlights
Discovery of a novel lineage of regulatory T (Treg) cells, which are CD4+FoxA1+, as major regulators of responsiveness to interferon beta (IFN-β) therapy in patients with relapsingremitting multiple sclerosis (RRMS), is important for further optimization of this first in class diseasemodifying therapy (DMT)
Data from RRMS tissue analysis and relapsing EAE are concurrent in identifying a CD4+ T cell-specific chemotactic factor, interleukin 16 (IL-16), as a key regulator of progressive central nervous system (CNS) inflammation mediated by CD4+ Th1 cells
Concurrent with RRMS findings, in relapsing-remitting MOG35–55-induced EAE in (B6 × SJL) F1 (H-2b/s) mice, intra-CNS production of IL-16 correlates with extensive CD4+ T cell infiltration, accompanied by phosphorylation of axonal cytoskeleton, which all peak during relapses and in chronic progressive disease
Summary
Discovery of a novel lineage of regulatory T (Treg) cells, which are CD4+FoxA1+, as major regulators of responsiveness to IFN-β therapy in patients with relapsingremitting multiple sclerosis (RRMS), is important for further optimization of this first in class diseasemodifying therapy (DMT). 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.
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