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 9

Mtb downregulates ANXA1 in human blood monocyte–derived DCs.

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Mtb downregulates ANXA1 in human blood monocyte–derived DCs. (A) Box plo...
(A) Box plots showing log2 expression levels of ANXA1 (y axis) in noninfected and Mtb-infected DCs. (B) Gene regulatory network of ANXA1-associated genes. We identified 18 genes for which expression levels were significantly associated with the levels of ANXA1 in Mtb-infected DCs. The thickness of the edges connecting the nodes in the network (i.e., genes) reflects the strength of the association of these genes with ANXA1 as well as among themselves. Only connections with an r2 value above 0.2 are shown. Genes associated with the endosome membrane and the lysosome pathways are highlighted. (C and D) Annexin1 mediates autophagy in DCs. (C) DCWT or DCAnxa1–/– were cultured with vehicle or the mTOR inhibitor rapamycin for 6 hours. Bafilomycin A1 was added 2 hours prior to cell lysis and Western blots for LC3B, phospho-S6 (pS6), and β-tubulin. (D) The means of bafilomycin-induced fold increase in LC3B-II levels ± SEM (ΔLC3BII), each obtained from 6 individual experiments. * P < 0.05, KO vs. WT (t test).