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-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.