IL-23p19 and CD5 antigen-like form a possible novel heterodimeric cytokine and contribute to experimental autoimmune encephalomyelitis development

Abstract

Among various cytokines, interleukin (IL)-12 family cytokines have very unique characteristics in that they are composed of two distinct subunits and these subunits are shared with each other. IL-23, one of the IL-12 family cytokines, consists of p19 and p40 subunits, is mainly produced by antigen-presenting cells, and plays a critical role in the expansion and maintenance of pathogenic helper CD4+ T (Th)17 cells. Since we initially found that p19 is secreted in the culture supernatant of activated CD4+ T cells, we have further investigated the role of p19. p19 was revealed to associate with CD5 antigen-like (CD5L), which is a repressor of Th17 pathogenicity and is highly expressed in non-pathogenic Th17 cells, to form a composite p19/CD5L. This p19/CD5L was shown to activate STAT5 and enhance the differentiation into granulocyte macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells. Both CD4+ T cell-specific conditional p19-deficient mice and complete CD5L-deficient mice showed significantly alleviated experimental autoimmune encephalomyelitis (EAE) with reduced frequency of GM-CSF+CD4+ T cells. During the course of EAE, the serum level of p19/CD5L, but not CD5L, correlated highly with the clinical symptoms. Thus, the composite p19/CD5L is a possible novel heterodimeric cytokine that contributes to EAE development with GM-CSF up-regulation.

Multifaceted Roles of CD5L in Infectious and Sterile Inflammation

“…Both CD4+ T-cell-specific conditional p19-deficient mice and complete CD5Ldeficient mice showed significantly alleviated EAE symptoms with a reduced frequency of GM-CSF + CD4+ T cells. All together, these studies reveal the p19/CD5L complex as a potential novel heterodimeric cytokine that contributes to EAE development [29].…”

“…Other studies also identified CD5L as a switch that regulates the functional state of helper CD4+ T (Th)17 cells and restrains their pathogenicity [28,29]. Th17 cells have diverse functions.…”

“…This effect of CD5L on lipid metabolism reduces Rorγt binding to the pathogenic IL-23r and IL-17 regions and increases its binding at the protective IL-10 region [28]. Additional studies revealed that the p19 subunit of IL-23, a cytokine that plays a critical role in the differentiation and maintenance of pathogenic Th17 cells, is secreted in the culture supernatant of activated CD4+ T cells and associates with CD5L to form a p19/CD5L heterodimer, which subsequently activates STAT5 and enhances differentiation into granulocyte macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells [29].…”

Neuroinflammation: Extinguishing a blaze of T cells

“…68,69 Soluble p19, a subunit of IL-23, binds CD5L to form a p19/CD5L dimer that activates STAT5 to promote ThGM-CSF differentiation. 70 Of note, polymorphism in IL-2RA is one of the highest genetic risk factors for MS, as well as IL-7RA. 10 Polymorphisms in IL-2RA are associated with higher production of GM-CSF by memory T cells in healthy individuals, and with increased clinical severity in MS patients.…”

Prospects for the use of monoclonal antibodies to interleukin 23 Gusеlkumab in psoriatic arthritis: New data

“…Последние, ингибируя экспрессию RORC, подавляют образование Th17-клеток, но под влиянием «провоспалительных» цитокинов могут трансформироваться в «патогенные» Th17-клетки -так называемый феномен «пластичности» Th17/Трег [12]. Выявлены дополнительные гены (Gpr65, Toso, Plzp), связанные с поддержанием «патогенности» Th17-клеток и CD5-антиген-подобный белок (CD5L, CD5 antigen-like), отменяющий патогенный потенциал Th17-клеток [13]. До недавнего времени предполагали, что Th17-клетки, индуцированные ТФР-β и ИЛ-6, обладают слабой «патогенностью» и не способны индуцировать аутоиммунную патологию.…”