The X-linked histone demethylases KDM5C and KDM6A as regulators of T cell-driven autoimmunity in the central nervous system

• Published in: Brain research bulletin Vol. 202; p. 110748
• Main Authors: Fazazi, Mohamed Reda, Ruda, Gian Filippo, Brennan, Paul E., Rangachari, Manu
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2023; Elsevier
• Subjects: Experimental autoimmune encephalomyelitis; KDM5c; KDM6A; Multiple sclerosis; Sex differences; Th17 cell; Experimental autoimmune encephalomyelitis; Sex differences; KDM5c; Multiple sclerosis; Th17 cell; KDM6A
• ISSN: 0361-9230; 1873-2747; 1873-2747
• DOI: 10.1016/j.brainresbull.2023.110748

T cell-driven autoimmune responses are subject to striking sex-dependent effects. While the contributions of sex hormones are well-understood, those of sex chromosomes are meeting with increased appreciation. Here, we outline what is known about the contribution of sex chromosome-linked factors to experimental autoimmune encephalomyelitis (EAE), a mouse model that recapitulates many of the T cell-driven mechanisms of multiple sclerosis (MS) pathology. Particular attention is paid to the KDM family of histone demethylases, several of which – KDM5C, KDM5D and KDM6A – are sex chromosome encoded. Finally, we provide evidence that functional inhibition of KDM5 molecules can suppress interferon (IFN)γ production from murine male effector T cells, and that an increased ratio of inflammatory Kdm6a to immunomodulatory Kdm5c transcript is observed in T helper 17 (Th17) cells from women with the autoimmune disorder ankylosing spondylitis (AS). Histone lysine demethlyases thus represent intriguing targets for the treatment of T cell-driven autoimmune disorders. •The incidence of relapse-onset multiple sclerosis is higher in women, yet men are at higher risk for progression.•The X-linked histone lysine demethylase KDM6A promotes T17 cell responses.•X-linked KDM5C represses Th17 responses.•Pharmacological inhibition of KDM5 molecules reduces IFNγ production from T cells.•Decreased KDM5C:KDM6A transcript ratio characterizes female Th17 cells in the autoimmune disease ankylosing spondylitis.