Dysregulated Stem Cell Niches and Altered Lymphocyte Recirculation Cause B and T Cell Lymphopenia in WHIM Syndrome

Overview

Journal Sci Immunol

Specialty Allergy & Immunology

Date 2022 Sep 23

PMID 36149943

Authors

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

Joao P Pereira

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system.

Jang G, Park R, Esteva E, Hsu P, Feng J, Upadhaya S J Exp Med. 2025; 222(6).

PMID: 40072317 PMC: 11899982. DOI: 10.1084/jem.20240587.

CXCR4 antagonism ameliorates leukocyte abnormalities in a preclinical model of WHIM syndrome.

Roland L, Nguyen C, Zmajkovicova K, Khamyath M, Kalogeraki M, Schell B Front Immunol. 2024; 15:1468823.

PMID: 39588369 PMC: 11586337. DOI: 10.3389/fimmu.2024.1468823.

CXCR4 signaling determines the fate of hematopoietic multipotent progenitors by stimulating mTOR activity and mitochondrial metabolism.

Rondeau V, Kalogeraki M, Roland L, Nader Z, Gourhand V, Bonaud A Sci Signal. 2024; 17(860):eadl5100.

PMID: 39471249 PMC: 11733996. DOI: 10.1126/scisignal.adl5100.

Triple burden of hepatitis B, hepatitis Delta viruses, and to pregnant women.

Eyi A, Komba O, Chambellant C, Mikelet Boussoukou I, Moukambi L, Moukambi K IJID Reg. 2024; 13:100447.

PMID: 39399128 PMC: 11471226. DOI: 10.1016/j.ijregi.2024.100447.

Distinct fibroblast functions associated with fibrotic and immune-mediated inflammatory diseases and their implications for therapeutic development.

Barron A, Fabre T, De S F1000Res. 2024; 13:54.

PMID: 38681509 PMC: 11053351. DOI: 10.12688/f1000research.143472.1.

References

Zehentmeier S, Pereira J . Cell circuits and niches controlling B cell development. Immunol Rev. 2019; 289(1):142-157. PMC: 6464388. DOI: 10.1111/imr.12749. View

Franzen O, Gan L, Bjorkegren J . PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data. Database (Oxford). 2019; 2019. PMC: 6450036. DOI: 10.1093/database/baz046. View

Gao J, Yim E, Siwicki M, Yang A, Liu Q, Azani A . Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model. J Clin Invest. 2018; 128(8):3312-3318. PMC: 6063486. DOI: 10.1172/JCI120375. View

Mendoza A, Fang V, Chen C, Serasinghe M, Verma A, Muller J . Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature. 2017; 546(7656):158-161. PMC: 5683179. DOI: 10.1038/nature22352. View

Pereira J, Xu Y, Cyster J . A role for S1P and S1P1 in immature-B cell egress from mouse bone marrow. PLoS One. 2010; 5(2):e9277. PMC: 2823786. DOI: 10.1371/journal.pone.0009277. View

Baryawno N, Przybylski D, Kowalczyk M, Kfoury Y, Severe N, Gustafsson K . A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell. 2019; 177(7):1915-1932.e16. PMC: 6570562. DOI: 10.1016/j.cell.2019.04.040. View

Mackay F, Majeau G, Lawton P, Hochman P, Browning J . Lymphotoxin but not tumor necrosis factor functions to maintain splenic architecture and humoral responsiveness in adult mice. Eur J Immunol. 1997; 27(8):2033-42. DOI: 10.1002/eji.1830270830. View

Balabanian K, Lagane B, Pablos J, Laurent L, Planchenault T, Verola O . WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12. Blood. 2004; 105(6):2449-57. DOI: 10.1182/blood-2004-06-2289. View

Knop L, Deiser K, Bank U, Witte A, Mohr J, Philipsen L . IL-7 derived from lymph node fibroblastic reticular cells is dispensable for naive T cell homeostasis but crucial for central memory T cell survival. Eur J Immunol. 2020; 50(6):846-857. DOI: 10.1002/eji.201948368. View

10.

Cheng H, Onder L, Novkovic M, Soneson C, Lutge M, Pikor N . Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp. Nat Commun. 2019; 10(1):1739. PMC: 6465367. DOI: 10.1038/s41467-019-09728-3. View

11.

Mandal M, Okoreeh M, Kennedy D, Maienschein-Cline M, Ai J, McLean K . CXCR4 signaling directs Igk recombination and the molecular mechanisms of late B lymphopoiesis. Nat Immunol. 2019; 20(10):1393-1403. PMC: 6754289. DOI: 10.1038/s41590-019-0468-0. View

12.

Miao R, Lim V, Kothapalli N, Ma Y, Fossati J, Zehentmeier S . Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory. Front Immunol. 2020; 11:600127. PMC: 7726109. DOI: 10.3389/fimmu.2020.600127. View

13.

Pereira J, An J, Xu Y, Huang Y, Cyster J . Cannabinoid receptor 2 mediates the retention of immature B cells in bone marrow sinusoids. Nat Immunol. 2009; 10(4):403-11. PMC: 2768754. DOI: 10.1038/ni.1710. View

14.

Nie Y, Han Y, Zou Y . CXCR4 is required for the quiescence of primitive hematopoietic cells. J Exp Med. 2008; 205(4):777-83. PMC: 2292218. DOI: 10.1084/jem.20072513. View

15.

Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B . Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J Immunol. 2011; 188(1):497-503. DOI: 10.4049/jimmunol.1102321. View

16.

Nie Y, Waite J, Brewer F, Sunshine M, Littman D, Zou Y . The role of CXCR4 in maintaining peripheral B cell compartments and humoral immunity. J Exp Med. 2004; 200(9):1145-56. PMC: 2211858. DOI: 10.1084/jem.20041185. View

17.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

18.

Upadhaya S, Krichevsky O, Akhmetzyanova I, Sawai C, Fooksman D, Reizis B . Intravital Imaging Reveals Motility of Adult Hematopoietic Stem Cells in the Bone Marrow Niche. Cell Stem Cell. 2020; 27(2):336-345.e4. PMC: 7415613. DOI: 10.1016/j.stem.2020.06.003. View

19.

Dejardin E, Droin N, Delhase M, Haas E, Cao Y, Makris C . The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity. 2002; 17(4):525-35. DOI: 10.1016/s1074-7613(02)00423-5. View

20.

Beck T, Gomes A, Cyster J, Pereira J . CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow. J Exp Med. 2014; 211(13):2567-81. PMC: 4267240. DOI: 10.1084/jem.20140457. View