Its binding groove contains clearly defined A and F pocket with no accessory portals (Salio et al. of innate and adaptive immunity. While CD1 system may be involved in numerous infectious, inflammatory, and autoimmune diseases, its involvement may lead to opposite outcomes depending on different pathologies. Despite these ambiguities and complexity, CD1 system draws growing attention and continues to show glimmers of therapeutic potential. In this review, we summarize the current knowledge about CD1 proteins, their structures, lipid-binding profiles, and roles in immunity, and evaluate the role of CD1 proteins in eliciting humoral immune response. Keywords: CD1 proteins, 3-Formyl rifamycin Antigen presentation, iNKT cells, Glycosphingolipids Introduction Major histocompatibility complex (MHC) proteins play an essential role in gnathostome immune system by presenting antigens to T cells. The mainstream part of that mechanism involves presentation of peptide antigens in two possible ways depending on their origin. Proteins derived from phagocytosed pathogens (e.g., from bacteria or fungi) 3-Formyl rifamycin are degraded in the lysosomes: the remnant peptides may be captured by the MHC Class II proteins and trafficked to the cell surface to engage helper T cells. Endogenous proteins, both self and foreign, e.g., viral or FLNC derived from intracellular bacteria, undergo degradation in proteasomes, in which case the resulting peptides are carried to the cell surface by MHC Class I. The displayed fragments are then probed by cytotoxic T cells (Neefjes and Ovaa 2013). However, self-versus-foreign discrimination is not limited to processing and presentation of proteins, but involves lipids as well. Lipid antigens are presented by a distinct family of MHC Class I-like proteins, named CD1 (Table?1). Humans express five isoforms of CD1 (CD1a-CD1e), in contrast to muroids, which express only CD1d isotype (Barral and Brenner 2007), and ruminants, which express all but CD1c (Van Rhijn et al. 2006). CD1d was previously reported to be missing in ruminants too (Van Rhijn et al. 2006; Looringh van Beeck et al. 2009), but recently, it has been shown that the bovine CD1D gene is expressed and the protein structure has been solved (Nguyen et al. 2013; Wang et al. 2012). Two chicken CD1 genes identified so far do not match to any of the mammalian isoforms, and are, therefore, named CD1.1 and CD1.2 (Miller et al. 2005; Salomonsen et al. 2005). Based on the amino-acid sequence, mammalian CD1 proteins have been classified into three groups: CD1a-c belong to group 1 and present lipid antigens to clonally diverse T cells that mediate adaptive immunity, while CD1d proteins make up group 2 and present antigens to natural killer T cells (NKT) (Cerundolo et al. 2009). A subset of these cells expresses an invariant T-cell receptor (TCR) antigens (Beckman et al. 1994). The first described lipid antigens recognized by CD1 system were (Tsuji 2006) (Table?2). CD1 isoforms show different and in some cases overlapping binding profiles, which are related to the architecture of their binding grooves (de Jong et al. 2007) and different trafficking routes through subcellular compartments, 3-Formyl rifamycin causing each isoform to encounter a different set of lipid species to the cell surface (Lawton and Kronenberg 2004) (Fig.?1). CD1a and (to a lesser extent) CD1c predominantly follow early endosomal pathways and recycle to the cell surface, while CD1b and CD1d efficiently proceed to late endosomes and lysosomes before resurfacing (Salamero et al. 2001; Van Rhijn et al. 2009). This difference may hint at how rodents could afford deleting their group 1 CD1 and partially explain the capacity of CD1d to compensate for the loss (Dascher and Brenner 2003). All CD1 molecules are heavily glycosylated type I integral membrane proteins, and each comprises extracellular sppMycolic acidsCD1bBeckman et al. 1994 BCG spp sppUrushiolCD1aKim et al. 2016 Mammalian (self)Wax estersTriacylglycerolsFree fatty acidsSqualeneCD1ade Jong et al. 2010 de Jong et al. 2014 SulfatideCD1a, b, cCD1dZajonc et al. 2003 Shamshiev et al. 2002 Bai et al. 2012 Isoglobotriaosylceramide (iGb3)CD1dZhou et al. 2004b GM1 gangliosideCD1bShamshiev et al. 2000 GQ1b gangliosideCD1bIshida et al. 1994 GD3 gangliosideCD1dWu et al. 2003 Mannosyl and spp., may also be presented by CD1b (Huang et al. 2011), raising a question of how such relatively small compounds remain accessible for the TCR rather than collapse inside the CD1b cleft. Presumably, this is achieved due to endogenous lipids, which assume the role of scaffolds. In the absence of a foreign ligand, spacious CD1b may be stuffed with two or more endogenous lipids. Smaller foreign ligands eject the endogenous lipids from the top of the cleft and sit on the lipids located deeper (usually a diacylglyceride or deoxydihydroceramide), which lend the foreign lipids upward support. Large foreign.