Di Lorenzo, B. | Search bioRxiv

bioRxiv2026

Regional macrophage specialization shapes intestinal neuroimmune function

Tissue-resident macrophages adapt to local environments to support organ-specific functions, but whether their regulation differs across regions of the same organ is poorly understood. The gastrointestinal tract provides an ideal system to address this question because its anatomically distinct regions perform specialized physiological functions and contain different cellular environments. Here, we found that intestinal muscularis macrophages (MMs) exhibited distinct regional trophic requirements and neuroimmune functions across the gut. Small-intestinal MMs were highly sensitive to CSF1 neutralization but recovered robustly, whereas colonic MMs were less sensitive to CSF1 depletion yet showed limited recovery. Disruption of CSF1-dependent MMs selectively reduced nitrergic neurons and altered motility in the small intestine, whereas the colonic neuronal compartment was comparatively preserved. Csf1 was enriched in small-intestinal nNOS+ neurons, and neuron-specific Csf1 deletion reduced both MMs and nitrergic neurons and altered small-intestinal transit, with limited effects in the colon. Together, these findings reveal that macrophage trophic requirements and neuroimmune functions are regionally specialized within the intestine and identify neuronal CSF1 as a key component of the trophic relationship between nitrergic neurons and MMs in the small intestine.

neuroscience↗

bioRxiv2021

Follicular helper T cell signature of replicative exhaustion, apoptosis and senescence in common variable immunodeficiency

BackgroundCommon variable immunodeficiency (CVID) is the most frequent primary antibody deficiency. A significant number of CVID patients are affected by various manifestations of immune dysregulation such as autoimmunity. Follicular T cells cells are thought to support the development of CVID by providing inappropriate signals to B cells during the germinal center (GC) response. ObjectivesWe determined the possible role of follicular helper (Tfh) and follicular regulatory T (Tfr) cells in patients with CVID by phenotypic, molecular, and functional studies. MethodsWe analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh cells in the peripheral blood of 27 CVID patients (11 pediatric and 16 adult) displaying autoimmunity as additional phenotype and compared them to 106 (39 pediatric and 67 adult) age-matched healthy controls. We applied Whole Exome Sequencing (WES) and Sanger sequencing to identify mutations that could account for the development of CVID and associate with Tfh alterations. ResultsA group of CVID patients (n=9) showed super-physiological frequency of Tfh1 cells and a prominent expression of PD-1 and ICOS, as well as a Tfh RNA signature consistent with highly active, but exhausted and apoptotic cells. Plasmatic CXCL13 levels were elevated in these patients and positively correlated with Tfh1 cell frequency, PD-1 levels, and an elevated frequency of CD21loCD38lo autoreactive B cells. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were ideintified in four patients belonging to this group. Lymphocytes with highly shortened telomeres, and a Tfh signature enriched in genes involved in telomere elongation and response to DNA damage were seen. Histopathological analysis of the spleen in one patient showed reduced amount and size of the GC that, unexpectedly, contained an increased number of Tfh cells. ConclusionThese data point toward a novel pathogenetic mechanism in a group of patients with CVID, whereby alterations in DNA repair and telomere elongation might be involved in GC B cells, and acquisition of a Th1, highly activated but exhausted and apoptotic phenotype by Tfh cells.

immunology↗