Access of soluble antigens to the endoplasmic reticulum can explain cross-presentation by dendritic cells

Speaker: 方宜婷                            Date: PM 1:00-2:00; 03/23/2005

Commentator: 蕭璦莉 老師                  Room: 601

Abstract:

        Dendritic cells (DCs) are crucial for the priming of CTL response to many infectious pathogens. However, for pathogens that don’t infect DCs or that inhibit DC function, DCs can present exogenous antigens associated with MHC class I by a process called “cross-presentation”. In previous studies of DCs and macrophages, the ER functioned as a membrane donor during phagocytosis (1). The ER membranes delivered all elements which were required for MHC class I antigen processing to early phagosome (2). This phenomenon could offer the model of how particulate molecules were cross-presented by MHC class I processing. Nevertheless, it couldn’t explain cross-presentation of soluble antigens, whose endocytosis was not known to involve recruitment of ER membrane. In this study, the authors used truncated US6 as soluble exogenous antigens. US6, from human cytomegalovirus, blocked TAP-mediated peptide transport by interacting with the lumenal region of the TAP heterodimer. The results showed that exogenous US6 proteins accessed the ER lumen and inhibited MHC class I expression. Being unable to monitor the trafficking of internalized US6 by microscopy, the authors chose to a protease-resistant protein b2-microglobulin (b2M) by incubating DCs from b2M-deficient mice with human b2M. The exogenous b2M rescued MHC class I expression in b2M-deficient DCs by priming with MHC class I heavy chains in the ER and facilitating their transport to the cell surface. These data indicated that exogenous b2M and, by analogy, US6, would enter the ER lumen. Furthermore, exogenous US6 inhibited endogenous antigen presentation. Taken together, these findings provide evidence that soluble exogenous proteins can have access to the ER in DCs. This cross-presentation pathway may facilitate the proper balance of immune activation and tolerance (3).

References:

1.      Gagnon, E. et al. Endoplasmic reticulum-mediated phagocytosis is a mechanism of entry into macrophages. Cell 110, 119-131 (2002).

2.      Ackerman, A. L. and Cresswell, P. Cellular mechanisms governing cross-presentation of exogenous antigens. Nat. Immunol. 5, 678-684 (2004).

3.      Ackerman, A. L. et al. Access of soluble antigens to the endoplasmic reticulum can explain cross-presentation by dendritic cells. Nat. Immunol. 6, 107-113 (2005).