Hypoxia‐inducible factor‐1 (HIF‐1) is a heterodimeric (HIF‐1α/ HIF‐1β) transcription factor in which the oxygen‐sensitive HIF‐1α subunit regulates gene transcription to mediate adaptive tissue responses to hypoxia. HIF‐1 is a key mediator in both regulatory and pathogenic immune responses, because ongoing inflammation in localized tissues causes increased oxygen consumption and consequent hypoxia within the inflammatory lesions. In autoimmune diseases, HIF‐1 plays complex and divergent roles within localized inflammatory lesions by orchestrating a critical immune interplay sponsoring the pathogenesis of the disease. In this review, we have summarized the role of HIF‐1 in lymphoid and myeloid immunomodulation in autoimmune diseases. HIF‐1 drives inflammation by controlling the Th17/T_reg/Tr1 balance through the tipping of the differentiation of CD4⁺ T cells in favour of pro‐inflammatory Th17 cells while suppressing the development of anti‐inflammatory T_reg/Tr1 cells. On the other hand, HIF‐1 plays a protective role by facilitating the expression of anti‐inflammatory cytokine IL‐10 in and expansion of CD1d^hiCD5⁺ B cells, known as regulatory B cells or B10 cells. Apart from lymphoid cells, HIF‐1 also controls the activation of macrophages, neutrophils and dendritic cells, thus eventually further influences the activation and development of effector/regulatory T cells by facilitating the creation of a pro/anti‐inflammatory microenvironment within the autoinflammatory lesions. Based on the critical immunomodulatory roles that HIF‐1 plays, this master transcription factor seems to be a potent druggable target for the treatment of autoimmune diseases.

This study introduces a flexible format for tolerogenic vaccination that incorporates IFN-β and neuroantigen (NAg) in the Alum adjuvant. Tolerogenic vaccination required all three components, IFN-β, NAg, and Alum, for inhibition of experimental autoimmune encephalomyelitis (EAE) and induction of tolerance. Vaccination with IFN-β + NAg in Alum ameliorated NAg-specific sensitization and inhibited EAE in C57BL/6 mice in pretreatment and therapeutic regimens. Tolerance induction was specific for the tolerogenic vaccine Ag PLP178-191 or myelin oligodendrocyte glycoprotein (MOG)35–55 in proteolipid protein– and MOG-induced models of EAE, respectively, and was abrogated by pretreatment with a depleting anti-CD25 mAb. IFN-β/Alum–based vaccination exhibited hallmarks of infectious tolerance, because IFN-β + OVA in Alum–specific vaccination inhibited EAE elicited by OVA + MOG in CFA but not EAE elicited by MOG in CFA. IFN-β + NAg in Alum vaccination elicited elevated numbers and percentages of FOXP3⁺ T cells in blood and secondary lymphoid organs in 2D2 MOG-specific transgenic mice, and repeated boosters facilitated generation of activated CD44^high CD25⁺ regulatory T cell (Treg) populations. IFN-β and MOG35–55 elicited suppressive FOXP3⁺ Tregs in vitro in the absence of Alum via a mechanism that was neutralized by anti–TGF-β and that resulted in the induction of an effector CD69⁺ CTLA-4⁺ IFNAR⁺ FOXP3⁺ Treg subset. In vitro IFN-β + MOG–induced Tregs inhibited EAE when transferred into actively challenged recipients. Unlike IFN-β + NAg in Alum vaccines, vaccination with TGF-β + MOG35-55 in Alum did not increase Treg percentages in vivo. Overall, this study indicates that IFN-β + NAg in Alum vaccination elicits NAg-specific, suppressive CD25⁺ Tregs that inhibit CNS autoimmune disease. Thus, IFN-β has the activity spectrum that drives selective responses of suppressive FOXP3⁺ Tregs.