Immunomodulation effects of certain oxysterols were previous
Immunomodulation effects of certain oxysterols were previously shown to depend on activation of oxysterol-binding liver X receptors (LXRs). Recent work from our labs as well as from others has shown additional receptors linking oxysterols and immunity. For example, we found that 7α,25-dihydroxycholesterol as a key molecule involved in directing the migration of naive B cells, T cells and dendritic cells by engaging an orphan GPCR, GPR183, a gene which was initially found to be highly induced by Epstein–Barr virus infection of B cells. In another study, an oxysterol was found to be the most potent endogenous ligand of RORγt, an orphan nuclear receptor whose activation is the key step in the downstream production of IL-17—a key inflammatory pathway in several autoimmune disorders. Thus, many new biological functions of oxysterols, especially their broad range of roles as signaling molecules in the innate and adaptive immune system continues to be discovered and hold the promise of finding new targets for the therapeutic intervention for autoimmune disorders such as psoriasis, RA, IBD, and MS.,
Introduction Studies in the past decade have established T follicular helper (Tfh) cells as the major CD4+ T cell subset providing help to B cells and promoting antibody responses (Crotty, 2014, Ma et al., 2012, Ueno et al., 2015). Tfh cells are essential for the formation of germinal centers (GCs), the site for the selection of high-affinity Asiatic acid and for the development of B cell memory (MacLennan, 1994, Vinuesa and Cyster, 2011). Tfh cells and their precursors are equipped with multiple features required for B cell help (Crotty, 2014, Ma et al., 2012, Ueno et al., 2015). Interleukin (IL) 21 secreted by Tfh cells potently promotes the growth, differentiation, and class-switching of B cells. Tfh cells in GCs express high levels of inducible co-stimulator (ICOS), a cell surface co-stimulatory molecule crucial for Tfh cell interactions with B cells. CD40 ligand (CD40L) expressed by Tfh cells provides signals to B cells through CD40 for their differentiation and class-switching. Tfh cell differentiation requires the expression of the transcription repressor B cell lymphoma 6 (Bcl-6) and, conversely, is suppressed by the transcription repressor B lymphocyte-induced maturation protein 1 (Blimp-1), a Bcl-6 antagonist. Whether naive CD4+ T cells commit to differentiate into the Tfh lineage is largely pre-determined during the first step, in which CD4+ helper T cells are primed by dendritic cells (DCs) (Vinuesa and Cyster, 2011). Upon interactions with antigen-presenting DCs, a fraction of CD4+ T cells upregulate the expression of chemokine receptor CXCR5 while downregulating CCR7 expression, partly through the upregulated expression of the transcription factors (TFs) Bcl-6 and Ascl2 (Baumjohann et al., 2011, Choi et al., 2011, Kerfoot et al., 2011, Kitano et al., 2011, Liu et al., 2012, Liu et al., 2014). Such changes in the chemokine receptor expression promote the migration of activated CD4+ T cells toward B cell follicles and interactions with B cells at the T-B border. Tfh precursors then increase Bcl-6 expression and eventually differentiate into mature Tfh cells (Vinuesa and Cyster, 2011). In humans, IL-12 secreted by DCs plays an important role during the first differentiation step. Among DC-derived cytokines, IL-12 is the most efficient at inducing human naive CD4+ T cells to express Tfh molecules, including CXCR5, ICOS, and IL-21, and to upregulate TFs important for Tfh cell differentiation, such as Bcl-6, Batf, and c-Maf (Ma et al., 2009, Schmitt et al., 2009, Schmitt et al., 2013, Schmitt et al., 2014). Children who lack the expression of a functional IL-12 receptor β1 chain display fewer CXCR5+ circulating Tfh (cTfh) cells and memory B cells, indicating that signaling through the IL-12 receptor is important for the development and/or maintenance of human Tfh cells (Schmitt et al., 2013). However, IL-12 signals also drive the differentiation program toward the T helper 1 (Th1) cell through the upregulation of the TF T-bet (Szabo et al., 2000). T-bet collaborates with STAT4 activated by IL-12 signals for the expression of interferon (IFN)-γ (Thieu et al., 2008). The produced IFN-γ further provides a positive feedback loop by enhancing T-bet expression through STAT1 activation (Afkarian et al., 2002, Ylikoski et al., 2005).