Antigen-Loading Compartments for Major Histocompatibility Complex Class II Molecules Continuously Receive Input from Autophagosomes

Abstract

Major histocompatibility complex (MHC) class II molecules present products of lysosomal proteolysis to CD4(+) T cells. Although extracellular antigen uptake is considered to be the main source of MHC class II ligands, a few intracellular antigens have been described to gain access to MHC class II loading after macroautophagy. However, the general relevance and efficacy of this pathway is unknown. Here we demonstrated constitutive autophagosome formation in MHC class II-positive cells, including dendritic, B, and epithelial cells. The autophagosomes continuously fuse with multivesicular MHC class II-loading compartments. This pathway was of functional relevance, because targeting of the influenza matrix protein 1 to autophagosomes via fusion to the autophagosome-associated protein Atg8/LC3 led to strongly enhanced MHC class II presentation to CD4(+) T cell clones. We suggest that macroautophagy constitutively and efficiently delivers cytosolic proteins for MHC class II presentation and can be harnessed for improved helper T cell stimulation.

Intersection of autophagy with pathways of antigen presentation

“…Interestingly, numerous examples exist of self and foreign intracellular antigens that are presented by MHCII molecules (Nimmerjahn et al, 2003;Dorfel et al, 2005;Paludan et al, 2005;Schmid et al, 2007;Riedel et al, 2008;Jagannath et al, 2009). How do these antigens access endosomal MHCII loading compartments (termed MIIC)?…”

“…Given the trafficking route of autophagosomes from cytosol to lysosomes, autophagy is implicated in the delivery of cytosolic antigen to the MIIC. Indeed, immature and mature human monocyte-derived dendritic cells (DC) undergo constitutive autophagy with the majority of autophagosomes fusing with MIIC (Schmid et al, 2007). For several antigens, a direct role for autophagy in MHCII antigen presentation has been demonstrated.…”

“…Fusing influenza matrix protein 1 (MP1) to LC3 targets MP1 to autophagosomes and improves MP1 presentation to, and activation of, antigen-specific CD4 + T cells (Schmid et al, 2007). Furthermore, upregulation of autophagy with rapamycin in murine macrophages and CD11c + conventional DC (cDC) infected with Mycobacterium tuberculosis (MTb) increases MHCII antigen presentation of the MTb secreted antigen, Ag85B (Jagannath et al, 2009).…”

“…For example, siRNA knockdown of Atg12 in an EBV-transformed bone marrow-derived lymphoblastoid cell line does not impair antigen-specific CD8 + T cell responses (Paludan et al, 2005). Autophagy inhibition with 3-MA or wortmannin has no effect on tyrosinase antigen presentation by HLA (Nimmerjahn et al, 2003), and targeting the influenza matrix protein 1 (MP1) to autophagosomes does not enhance IFNγ secretion by antigen-specific CD8 + T cells (Schmid et al, 2007).…”

Differential use of autophagy by primary dendritic cells specialized in cross-presentation

“…Autophagy enables cells to expand the repertoire of antigens presented via this pathway by delivering cytosolic material to endo-lysosomal compartments, where it can be used as a source of MHC II peptide ligands. [4][5][6] Another route for presentation of endocytosed antigens, in which autophagy has been suggested to participate, is cross-presentation. This is a pathway whereby antigens captured from the extracellular environment are trafficked to the cytosol for degradation, chiefly by the proteasome.…”