Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome

Sandra Zehentmeier, Vivian Y. Lim, Yifan Ma, Julia Fossati, Takeshi Ito, Yawen Jiang, Alexei V. Tumanov, Ho Joon Lee, Lukas Dillinger, Jihyun Kim, Krisztian Csomos, Jolan E. Walter, Jungmin Choi, João P. Pereira

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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 (LTβR) as a critical pathway promoting interleukin-7 (IL-7) down-regulation in MSCs. Blocking LTβR or CXCR4 signaling restored IL-7 production and B cell development in WHIM mice. LTβR 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 LTβR signaling in BM MSCs and SLO stromal cells limits the lymphocyte compartment size.

Original languageEnglish (US)
Article numbereabo3170
JournalScience Immunology
Issue number75
StatePublished - Sep 2022
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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