Annexin1 regulates DC efferocytosis and cross-presentation during Mycobacterium tuberculosis infection
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
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
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 8

Reduced expression of MHC-I/peptide complex and antigen processing by Anxa1–/– DCs.

Options: View larger image (or click on image) Download as PowerPoint
Reduced expression of MHC-I/peptide complex and antigen processing by An...
(A and B) BMDCWT and DCAnxa1–/– were incubated with 10 mg/ml of OVA protein or 10–5 μM SIINFEKL or infected in vitro with BCG-OVA (MOI ~10). After 16 hours, expression of H-2Kb–SIINFEKL complex was measured on the cell surface. (A) Histogram of stimulated cells (SIINFEKL, blue; OVA protein, red; BCG-OVA, purple) versus unstimulated cells (black). (B) MFI of expression of H-2Kb–SIINFEKL complex on the surface of DCWT and DCAnxa1–/–. Results are representative of 3 independent experiments. *P < 0.05 (1-way ANOVA). (C and D) 105 BMDCs were loaded with 15 μg/ml of a quenched OVA protein (DQ-OVA). Antigen processing was quantified as increase in MFI after 30 minutes. Controls were cells loaded with DQ-OVA for 15 minutes on ice. Results are representative of 3 to 6 independent experiments. *P < 0.05 (t test, 1 tailed). (E–G) 20 μg of DQ-OVA were injected (intranasal) into WT and Anxa1–/– mice. Two hours later, lung cells were stained for DCs (CD11c+MHC-IIhi) (E), and degradation of DQ-OVA was evaluated on this cell population as increase in MFI (F and G). Numbers above outlined areas (E) indicate the percentage of CD11c+MHC-IIhi cells. Results are representative of 2 independent experiments. *P < 0.05 (t test).