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.
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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

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Figure 5

Expression of annexin1 on apoptotic vesicles regulates efferocytosis.

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Expression of annexin1 on apoptotic vesicles regulates efferocytosis. (A...
(A and B) In vitro efferocytosis assay with WT BMDCs. (A) Confocal microscopy of WT BMDCs (DCWT) incubated with PKH26-labeled WT (upper panel) or Anxa1–/– (bottom panel) apoptotic vesicles (red). DCWT were stained for F-actin (green) and nuclei (blue). The right pictures represent an overlay demonstrating the presence of red vesicles in the cytoplasm of DCWT. Scale bars: 20 μm. (B) Percentage of DCWT-containing vesicles in the cytoplasm. Results are representative of 2 independent experiments. **P < 0.01 (t test). (C–E) PKH26-labeled WT or Anxa1–/– vesicles mixed or not with recombinant annexin1 were injected into the footpad of WT mice (n = 3/group). (C, upper panels). Frequency of DCs (CD11c+MHC-IIhi) from popLNs after 24 hours of injection of apoptotic vesicles. Frequency of DCs (C, lower panels, and D) and CD8+ DCs (E) positive for PKH26. Numbers above outlined areas (C, upper panels) indicate the percentage of CD11c+MHC-IIhi cells. Numbers above gates (C, lower panels) indicate the percentage of CD11c+PKH26+ cells. *P < 0.05 (t test).