| First Author | Zehentmeier S | Year | 2022 |
| Journal | Sci Immunol | Volume | 7 |
| Issue | 75 | Pages | eabo3170 |
| PubMed ID | 36149943 | Mgi Jnum | J:339144 |
| Mgi Id | MGI:7517259 | Doi | 10.1126/sciimmunol.abo3170 |
| Citation | Zehentmeier S, et al. (2022) Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome. Sci Immunol 7(75):eabo3170 |
| abstractText | Gain-of-function (GOF) mutations in CXCR4 cause WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, characterized by infections, leukocyte retention in bone marrow (BM), and blood leukopenias. B lymphopenia is evident at early progenitor stages, yet why do CXCR4 GOF mutations that cause B (and T) lymphopenia remain obscure? Using a CXCR4 R334X GOF mouse model of WHIM syndrome, we showed that lymphopoiesis is reduced because of a dysregulated mesenchymal stem cell (MSC) transcriptome characterized by a switch from an adipogenic to an osteolineage-prone program with limited lymphopoietic activity. We identify lymphotoxin beta receptor (LTbetaR) as a critical pathway promoting interleukin-7 (IL-7) down-regulation in MSCs. Blocking LTbetaR or CXCR4 signaling restored IL-7 production and B cell development in WHIM mice. LTbetaR blocking also increased production of IL-7 and B cell activating factor (BAFF) in secondary lymphoid organs (SLOs), increasing B and T cell numbers in the periphery. These studies revealed that LTbetaR signaling in BM MSCs and SLO stromal cells limits the lymphocyte compartment size. |
