Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection
Fanny Tzelepis, … , Luis Bruno Barreiro, Maziar Divangahi
Fanny Tzelepis, … , Luis Bruno Barreiro, Maziar Divangahi
Published December 22, 2014
Citation Information: J Clin Invest. 2015;125(2):752-768. https://doi.org/10.1172/JCI77014.
View: Text | PDF
Research Article Infectious disease

Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection

Abstract

The phagocytosis of apoptotic cells and associated vesicles (efferocytosis) by DCs is an important mechanism for both self tolerance and host defense. Although some of the engulfment ligands involved in efferocytosis have been identified and studied in vitro, the contributions of these ligands in vivo remain ill defined. Here, we determined that during Mycobacterium tuberculosis (Mtb) infection, the engulfment ligand annexin1 is an important mediator in DC cross-presentation that increases efferocytosis in DCs and intrinsically enhances the capacity of the DC antigen–presenting machinery. Annexin1-deficient mice were highly susceptible to Mtb infection and showed an impaired Mtb antigen–specific CD8+ T cell response. Importantly, annexin1 expression was greatly downregulated in Mtb-infected human blood monocyte–derived DCs, indicating that reduction of annexin1 is a critical mechanism for immune evasion by Mtb. Collectively, these data indicate that annexin1 is essential in immunity to Mtb infection and mediates the power of DC efferocytosis and cross-presentation.

Authors

Fanny Tzelepis, Mark Verway, Jamal Daoud, Joshua Gillard, Kimya Hassani-Ardakani, Jonathan Dunn, Jeffrey Downey, Marilena Elena Gentile, Joanna Jaworska, Anthony Michel Jean Sanchez, Yohann Nédélec, Hojatollah Vali, Maryam Tabrizian, Arnold Scott Kristof, Irah Luther King, Luis Bruno Barreiro, Maziar Divangahi

×

Figure 10

Regulatory role of annexin1 during Mtb infection.

Options: View larger image (or click on image) Download as PowerPoint
Regulatory role of annexin1 during Mtb infection. Mtb-infected macrophag...
Mtb-infected macrophages undergoing apoptosis express annexin1 on the cell surface, which acts as an engulfment ligand. Bystander macrophages recognize this ligand and engulf apoptotic cells/vesicles containing live bacteria via efferocytosis to eliminate Mtb. Similarly, DCs recognize annexin1 and uptake apoptotic vesicles containing mycobacterial antigens. Mtb antigens are processed and loaded on MHC-I via cross-presentation. The presence of annexin1 on efferosomes, as well as in cytosol, may facilitate cross-presentation by increasing the availability of antigens in efferosomes to MHC-I, either via proteasome-ER–dependent pathway or/and vacular-dependent pathway (effero-lysosome). This will result in CD8+ T cell activation and expansion to control Mtb infection.