CXCR4 antagonism restores dendritic cell migration and activation in a WHIM syndrome mouse model

Abstract

WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a primary immunodeficiency caused by gain-of-function in CXCR4 chemokine receptor (CXCR4GOF) in response to its chemokine ligand CXCL12. The patients suffering from this syndrome display lymphopenia and neutropenia, and most of them show exacerbated susceptibility to human papillomavirus pathogenesis. In a mouse model harboring a WHIM-associated CXCR4 mutation and expressing HPV16 oncoproteins in keratinocytes, we previously reported reduced circulating plasmacytoid dendritic cells (pDCs), mirroring patients blood, and impaired dendritic cell (DC) trafficking from the skin to lymphoid organs, with the few migrating DCs displaying an overactivated phenotype. Given the promising results of CXCR4-targeted therapies in WHIM patients, we investigated whether and how the orally available CXCR4-specific antagonist, X4-136, affects DC localization, activation, and trafficking at the subset level, as well as skin immune landscape. CXCR4GOF inhibition corrected defects in circulating myeloid cells and pDCs, as well as in lymph node-resident DCs. Furthermore, it rescued skin DC migration to lymph nodes in WHIM mice, in a context- and subset-dependent manner, by promoting their activation and relocation within the dermis. Taken together, these findings indicate that inhibiting CXCR4GOF may restore skin immunity in WHIM syndrome by rescuing DC counts and functions. Key pointsO_LICXC R4 gain-of-function inhibition promotes subset-selective dermal dendritic cell migration to lymph nodes in a WHIM syndrome mouse model. C_LIO_LIInhibiting CXCR4 corrects migratory WHIM dendritic cell hyperactivation with subset-specific effects tied to the inflammatory context. C_LI