Modulation of autophagy affects ADCC in a tissue-specific manner
NUGUE M. 1, KOUMANTOU D. 1, BOISEL E. 1, LOTERSZTAJN S. 1, SAVEANU L. 1
1 INSERM UMR1149, Centre de Recherche sur l'Inflammation , Paris, France
Fc immunoglobulin G receptor (FcgRs) are essential to mediate the antibody-dependent cellular cytotoxicity (ADCC) induced by therapeutical antibodies. Recent data have shown that after their cross-linking by immune complexes, FcgRs are internalized in endosomes, from where they continue to signal for longer time periods, up to 2 hours after receptor internalization. We showed in vitro that FcgR endosomal signaling is necessary and essential to mediate different effector functions, such as pro-inflammatory cytokines secretion or ADCC.
Considering that ensodomal and autophagosomal pathway are inherently linked at multiple steps, we hypothesized that the autophagic flux modulation will affect the FcgRs endosomal signaling and, consequently, FcgRs effector functions. To investigate this hypothesis, we performed 2 different models of ADCC in vivo: B cell depletion in spleen and tumor cell depletion in the peritoneum. These 2 ADCC models were applied tos mice genetically modified for autophagy in macrophages: ATG5LysM-Cre+ mice, which have a defective autophagy and Rubicon LysM-Cré+ mice, in which autophagy induction and flux are facilitated. In the B cell depletion model, we observed that autophagy is required for ADCC function in splenic macrophages. On the contrary, in an intraperitoneal model of ADCC, autophagy is not involved.
These results indicate that, according to their tissular localization, the mechanisms involved in ADCC function are different. Although this may be surprising, our results are in agreement with the concept of “tissues-specificity of macrophages”, recently described in the literature. We also observed tissue-specificity for particular phenotypes induced by autophagy modulation, such as a more inflammatory phenotype for autophagy-deficient peritoneal macrophages. However, this pro-inflammatory phenotype does not lead to a more efficient ADCC function of autophagy-deficient peritoneal macrophages. By undergoing RNAseq analyses, we explore the mechanisms underlying tissue-specific involvement of autophagy in ADCC function of mouse macrophages.