Biology subjects

Pedroza, L.

Publications and source records attributed to Pedroza, L..

3 recordsLinked to original sources

bioRxiv2026

CXCR4 coordinates adhesion, migration, and development of human NK cells

Natural killer (NK) cells undergo stepwise differentiation from multipotent progenitors within secondary lymphoid tissues. Despite the central importance of the tissue microenvironment in their development, little is known about cell-cell interactions that regulate human NK cell trafficking and maturation. Here, we identify the chemokine receptor CXCR4 and its lig- and CXCL12 as regulators of stromal-NK cell interactions required for NK cell maturation. We demonstrate that CXCR4 is expressed throughout human NK cell development in peripheral blood and tonsil, and CXCL12 is enriched in stromal niches containing developing NK cells. Pharmacologic blockade or genetic disruption of CXCR4 resulted in diminished adhesion to integrin ligands and high-resolution imaging demonstrated crosstalk between CXCR4 and integrins, providing a mechanistic basis for chemokine-dependent modulation of adhesion. Further, CXCR4 blockade resulted in altered contact-dependent motility on stromal cells and integrin ligands, with decreased stable stromal engagement and increased cell speed. Consistent with a requirement for these interactions, treatment with the CXCR4 antagonist plerixafor (AMD3100) impaired NK cell generation from CD34+ precursors. Analysis of NK cells from WHIM syndrome patients with CXCR4 gain-of-function mutations treated with plerixafor revealed similar defects in migration and adhesion, supporting the in-vivo relevance CXCR4-dependent regulation of NK cell adhesion and motility.

immunology↗

bioRxiv2026

Autosomal dominant CDC45 deficiency with allelic expression bias causes a novel genetic disease of the immune system

Here we describe a damaging heterozygous variant in CDC45 in an individual with common variable immunodeficiency (CVID) and recurrent viral infections. This individual has variably decreased number of circulating NK cells, disruption in the ratio of CD56bright to CD56dim cells, and consistently decreased NK cell function. Interestingly, the inherited CDC45 variant is also present in a sibling with less severe clinical manifestations; we determined that allelic bias of the damaging allele accounts for this differential expressivity. As previously reported for other helicase variants that cause inborn errors of immunity (IEI), we found cell cycle defects in immune cells from the proband that lead to reduced survival of NK cells. Together, these findings link another member of the core replicative helicase complex to inborn errors of immunity and highlight the sensitivity of NK cells to these variants. They also define another case of allelic bias contributing to variable expressivity of an IEI gene.

immunology↗

bioRxiv2024

A mouse model of cardiac AL amyloidosis unveils mechanisms of tissue accumulation and toxicity of amyloid fibrils

AL amyloidosis is one of the most common types of systemic amyloidosis, caused by the deposition in tissues of fibrillar aggregates of abnormal immunoglobulin (Ig) light chain (LC), leading to organ dysfunction. The most frequent and severe forms affect the kidneys and heart, the latter being associated with a poor prognosis. Despite extensive efforts to decipher the mechanisms of fibril formation and their toxicity, the lack of reliable in vivo models hinders the study of the disease in its physiological context. We developped a transgenic mouse model producing high amounts of a human AL light chain (LC). While mice exceptionnaly develop spontaneous AL amyloidosis and do not exhibit organ toxicity due to the circulating amyloidogenic free LC, a single injection of amyloid fibrils, made up of the variable domain (VL) of the human LC, or soluble VL led to amyloid deposits in the heart, vessels, spleen and, to a lesser extent, in the kidney and other visceral tissues. AL fibrils in mice contain both full length and fragmented LC with a fragmentation pattern highly superposable to that of human AL fibrils from the same LC subgroup (IGLV6-57). They also develop an early cardiac dysfunction closely resembling the human disease with increased NT-proBNP,and activation of pathways involved in the extracellular matrix remodeling and fibrosis. Overall, this transgenic AL model closely reproduces human cardiac AL amyloidosis and shares with humans the biochemical composition of the deposits, arguing for a conserved mechanism of amyloid fibrils formation. It also shows that a partial degradation of the LC is likely required to initiate amyloid fibril formations. This model offers a new avenue for research on AL amyloidosis and fills an important gap for the preclinical evaluation of new therapies.

pathology↗