Khamyath, M. | bioRxiv Science

bioRxiv2024

Plasma cell heterogeneity is driven by type of immune challenge

Plasma cells play an essential role in humoral immunity, but many questions remain regarding the heterogeneity of this population, both in terms of ontogeny and involvement in the immune response. In this work, we have identified 5 subsets of plasma cells in human and mouse lymphoid tissues. These subpopulations were distinguished by differential expression of CD62L, CXCR4, Fc{gamma}RIIb and CD93. The antigenic context as well as the B cell of origin directed plasma cell differentiation towards specific subtypes that display distinct migratory and survival abilities in vivo. Altogether, ours results unveil that plasma cell phenotypic and functional heterogeneity relies on intrinsic imprinting during B cell activation.

immunology↗

bioRxiv2023

CXCR4 signaling strength regulates hematopoietic multipotent progenitor fate through extrinsic and intrinsic mechanisms

How cell-extrinsic niche-related and cell-intrinsic cues drive lineage specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow (BM) is partly understood. We show that CXCR4 signaling strength regulates localization and fate of MPPs. In mice phenocopying the BM myeloid skewing of patients with WHIM Syndrome (WS), a rare immunodeficiency caused by gain-of-function CXCR4 mutations, enhanced mTOR signaling and overactive Oxphos metabolism were associated with myeloid rewiring of lymphoid-primed MPPs (or MPP4). Fate decision of MPP4 was also affected by molecular changes established at the MPP1 level. Mutant MPP4 displayed altered BM localization relative to peri-arteriolar structures, suggesting that extrinsic cues contribute to their myeloid skewing. Chronic treatment with CXCR4 antagonist AMD3100 or mTOR inhibitor Rapamycin rescued lymphoid capacities of mutant MPP4, demonstrating a pivotal role for the CXCR4-mTOR axis in regulating MPP4 fate. Our study thus provides mechanistic insights into how CXCR4 signaling regulates the lymphoid potential of MPPs.

cell biology↗