A few antigen-loaded and all antigen unloaded MHC class I molecules are conveyed to late endosomes for their degradation. was termed as cross-priming. Thus cross-priming is defined as the activation of naive CD8+ T cells by antigen-presenting cells (APCs) that have acquired antigens from another cell. The mechanism of Thymalfasin cross-presentation was dubious such that the exogenous antigens would present on MHC I molecule eliciting an immune response that could lead to the death of otherwise healthy CTLs. Despite this anticipation, the cross-presentation phenomenon was confirmed and indeed some unique cells from lymphoid organs when explanted generated class I presented peptides. A later report showed the depletion of macrophages using silica hence reduced the ability of mice (C57BL/6) to generate CTL response even to live viruses. This indicates that macrophages, in general, may be key components in the initiation of all CTL responses [21]. Further experiments have also demonstrated cross-presentation of exogenous Thymalfasin cellular antigens by DCs and macrophages [22,23]. Regulation of antigen cross-presentation Intracellular pathways governing cross-presentation Extensive studies have shown that peptides from an extracellular antigen are presented on MHC I molecules by a wide variety of mechanisms [24]. In contrast with the classical MHC presentation pathway, the molecular mechanisms that regulate cross-presentation are yet indistinguishable. A number of early studies provide evidence to indicate the occurrence of cross-presentation. An experiment performed by Pfeifer et al. [25], showed that despite inhibiting classical MHC I processing employing Brefeldin A and/or cycloheximide, phagocytosed recombinant antigens were presented on MHC I molecules. Two major mechanisms that have been qualified to further govern the fate of antigen for cross-presentation are as follows (Figure 1): (i) Vacuolar pathway: it is a mechanism wherein lysosomal proteases in the endocytic compartments help to catabolize the proteins which then get loaded on to MHC I molecules. One particular lysosomal protease Cathepsin S is known to play Thymalfasin a major role during the degradation of antigen for the vacuolar pathway of antigen cross-presentation. In a study performed by Shen et al. [26], cross-presentation of phagocytosed ovalbumin was found to be TAP independent, and antigenic peptides were generated directly inside the phagosome. This degradation of peptides inside the endocytic compartments was possible owing to Cathepsin S which is preferentially expressed in APCs. It was observed that this TAP-independent presentation was inhibited in cells that are genetically deficient in endosomal protease Cathepsin S [26]. Thus, these experiments validate the critical role of Cathepsin S in the vacuolar pathway of antigen cross-presentation. However, little information is available to substantiate the significance of vacuolar pathway and further investigations are warranted. (ii) Phagosome to cytosol pathway: it is another pathway in which antigens phagocytized into endosomes get transferred to cytosol where proteasome-mediated hydrolysis of antigen occurs. Subsequently, peptides are transported to ER by TAP transporter and get presented on MHC I molecule. Interestingly, it has been noted that some phagosomes also contained TAP molecules [27]. Hence, an alternative mechanism articulates that the antigen-derived peptides after proteasome degradation are transported back into the endosomal compartment where these peptides are trimmed via insulin-regulated aminopeptidase (IRAP) in the endosome instead of ERAP in the ER before loading on to MHC I. Open in a separate window Figure 1 An overview of the mechanisms of antigen cross-presentationVacuolar and Cytosolic cross-presentation pathways inside a DC: (1) Antigens internalized through phagocytosis or receptor-mediated endocytosis are properly degraded in the endosomes due to varying pH and different proteases. (2) Antigen is loaded on to recycled MHC I in the phagosome. (3) The recycling of MHC I is mediated through Rab11a in Toll-like receptor (TLR) controlled Serpinf2 process with the help of SNAP23 dependent on MyD88 signaling. (4) Alternatively, antigens processed under the cytosolic pathway are translocated to the cytosol via phagosomal disruption through NOX-2 complex and through Sec 61 translocon. (5) The antigens are lysed by proteasome complex. (6) Lysed antigens are transported to the ER via TAP transporter and further trimmed by ERAP and loaded on to MHC I. (7) Antigenic peptide in the cytosol after proteasomal degradation may also get retransported into phagosome through TAP which is further trimmed by IRAP and Thymalfasin presented on to recycled MHC-I molecule. (8) TAP molecule is transported from ER with the help of Sec22b protein resident of the ERGIC that interacts with Syntaxin 4 on phagosome. Abbreviation: ERGIC, ER-Golgi intermediate compartment. Processing and mechanism of antigen transfer from phagosome to the cytosol The antigenic peptides that get internalized by phagosome are processed before getting loaded.