Ce mois-ci, la SFI et le Club Français des Jeunes Immunologistes mettent en avant l’article publié dans Blood, du Dr. Vetillard, qui a fait sa thèse dans l’équipe du Pr. Schlecht-Louf, à l’Inserm UMR996, Clamart. L’article sera publié sur le site de la SFI durant tout le mois de juin et concourra pour le prix du  » Meilleur article doctorant » au mois d’octobre prochain.

 

Journal Blood. 2021 May 20;137(20):2770-2784.
Titre CXCR4 signaling controls dendritic cell location and activation at steady state and in inflammation
Auteurs Mathias Vétillard#, Carmen Gallego#, Joseph Calmette, Mélanie Roriz, Viviana Marin-Esteban, Maximilien Evrard, Marie-Laure Aknin, Nicolas Pionnier, Manon Lefrançois, Françoise Mercier-Nomé, Yves Bertrand, Felipe Suarez, Jean Donadieu, Lai Guan Ng, Karl Balabanian, Françoise Bachelerie, and Géraldine Schlecht-Louf

#Co-first authors, contributed equally to the work

Résumé Dendritic cells (DCs) encompass several cell subsets that collaborate to initiate and regulate immune responses. Proper DC localization determines their function and requires the tightly controlled action of chemokine receptors. All DC subsets express CXCR4, but the genuine contribution of this receptor to their biology has been overlooked. We addressed this question using natural CXCR4 mutants resistant to CXCL12-induced desensitization and harboring a gain of function that cause the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS), a rare immunodeficiency associated with high susceptibility to the pathogenesis of human papillomavirus (HPV). We report a reduction in the number of circulating plasmacytoid DCs (pDCs) in WHIM patients, whereas that of conventional DCs is preserved. This pattern was reproduced in an original mouse model of WS, enabling us to show that the circulating pDC defect can be corrected upon CXCR4 blockade and that pDC differentiation and function are preserved, despite CXCR4 dysfunction. We further identified proper CXCR4 signaling as a critical checkpoint for Langerhans cell and DC migration from the skin to lymph nodes, with corollary alterations of their activation state and tissue inflammation in a model of HPV-induced dysplasia. Beyond providing new hypotheses to explain the susceptibility of WHIM patients to HPV pathogenesis, this study shows that proper CXCR4 signaling establishes a migration threshold that controls DC egress from CXCL12-containing environments and highlights the critical and subset-specific contribution of CXCR4 signal termination to DC biology
Article https://doi.org/10.1182/blood.2020006675