| Autor: |
Zehentmeier, Sandra, Lim, Vivian Y., Ma, Yifan, Fossati, Julia, Ito, Takeshi, Jiang, Yawen, Tumanov, Alexei V., Lee, Ho-Joon, Dillinger, Lukas, Kim, Jihyun, Csomos, Krisztian, Walter, Jolan E., Choi, Jungmin, Pereira, João P. |
| Předmět: |
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| Zdroj: |
Science Immunology; 2022, Vol. 7 Issue 75, p1-17, 17p |
| Abstrakt: |
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. Subpar sustenance for lymphocytes: WHIM syndrome, a human inborn error of immunity featuring reduced numbers of circulating lymphocytes, is caused by gain-of-function mutations in CXCR4. Zehentmeier et al. investigated stromal cell abnormalities contributing to lymphopenia by analyzing gene expression by bone marrow mesenchymal stem cells (MSCs) in a mouse model of the R334X WHIM-inducing mutation. Bone marrow MSCs in the mutant mice exhibited reduced expression of the gene for IL-7, a cytokine critical for early B cell differentiation, because of excess signaling through the lymphotoxin beta receptor (LTβR). Reduced expression of the gene for IL-7 in bone marrow and impaired lymphocyte access to survival niches in secondary lymphoid organs contributed to the lymphopenia. These findings demonstrate that CXCR4 and LTβR are viable targets for therapies to ameliorate the immunodeficiency of WHIM syndrome. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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