Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Pereira, João

Abstract

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare congenital immunodeficiency caused by gain-of-function (GOF) mutations in CXCR4. Although respiratory infections are common in WHIM patients, the underlying mechanisms of susceptibility remain unclear. Using a mouse model of WHIM syndrome, we show that myelokathexis does not impair lung immune surveillance under homeostatic conditions. During acute viral and bacterial respiratory infections, neutrophils and monocytes are efficiently recruited from circulation into the lung vasculature and parenchyma. However, these cells fail to reach the airways due to their retention in adventitial cuffs enriched with CXCL12-producing fibroblasts, where potentially function as niches typically supporting long-lived local adaptive immune cells. This mislocalization delays early innate defense and enhances pathogen dissemination. Notably, treatment with a CXCR4 antagonist fully restored airway recruitment of neutrophils and monocytes in WHIM mice. These findings uncover a CXCR4-dependent defect in innate immune cell positioning and underscore the importance of spatial regulation of immune niches for effective host defense against respiratory pathogens.

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