Abstract
Treatment targeting CD226 can ameliorate experimental autoimmune encephalomyelitis (EAE), the widely accepted model of MS. However, the mechanisms still need to be elucidated. Here we showed that CD226 blockage by anti-CD226 blocking mAb LeoA1 efficiently promoted IL-10 production in human peripheral blood monocytes (PBMC) or in mixed lymphocyte culture (MLC) system, significantly induced the CD4+IL-10+ T cell differentiation while suppressing the generation of Th1 and Th17. Furthermore, CD226 pAb administration in vivo reduced the onset of EAE in mice by promoting IL-10 production and regulating T cell differentiation. Concomitantly, the onset and severity of EAE were reduced and the serum IL-10 expression levels were increased in CD226 knockout mice than that in control mice when both received EAE induction. These novel findings confirmed that CD226 played a pivotal role in mediating autoimmune diseases such as EAE. Furthermore, to our knowledge, we show for the first time that IL-10 is an important contributor in the inhibitory effects of CD226 ligation on EAE.
Highlights
CD4+ T lymphocytes play an important role in regulating host immune responses as well as inflammatory and autoimmune diseases
We found that CD226 mAb LeoA1 decreased IFN-γ, TNF-α, IL-12 and IL-23 but increased IL-10 secretion in both systems and only decreased IL-2 and IL-17 expression levels in mixed lymphocyte culture (MLC) system
By making a ratio of four representative cytokine expression levels between www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget the LeoA1 and SED groups, we found that LeoA1 exerted the regulatory function to a stable extent without being affected by time in the peripheral blood monocytes (PBMC) system (Figure 1C)
Summary
CD4+ T lymphocytes play an important role in regulating host immune responses as well as inflammatory and autoimmune diseases. As an important influencing factor, Th subsets differentiation disorders have been shown to be highly associated with the pathogenesis and progression of EAE [1]. Immune suppressive agent dihydroartemisinin was proved to be effective in ameliorating EAE by suppressing Th cell function, by abolishing Th17 differentiation [3]. Interleukin-10 (IL-10), a cytokine with antiinflammatory properties, plays a crucial role in preventing various inflammatory pathologies especially in tumor and autoimmune diseases [4, 5]. High IL-10 expression level within the central nervous system is considered to be important for the initiation of recovery from EAE [8]. IL-10deficient mice develop more severe EAE than wild-type (WT) mice [9], demonstrating its beneficial effects on the pathogenesis of EAE
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