Skip to content
DraconiticResearch
Search Sources API
190,332 studies31 sourcesUpdated 12 min ago
Peer-reviewedCC BY 4.0Frontiers in Immunology

A Zap70 gain-of-function mutation alters mouse thymic maturation

  • Inmaculada Vico-Barranco1,2
  • Fanghui Zhang3,4
  • Claude Grégoire3
  • Luis M. Fernández-Aguilar1,5
  • Mikel M. Arbulo-Echevarria1,5
  • Isaac Narbona-Sánchez1,5
  • Raquel Muñoz-Fernández1,5
  • Bernard Malissen2,3,4,6
  • Marie Malissen2,3,4,6
  • Enrique Aguado1,5
6 affiliations
  1. 1Department of Biomedicine, Biotechnology and Public Health, Universidad de Cádiz
  2. 2Centre d’Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS
  3. 3Centre d’Immunologie de Marseille-Luminy (CIML), Aix Marseille Université, INSERM, CNRS
  4. 4School of Medical Technology, Xinxiang Medical University
  5. 5Institute of Biomedical Research Cadiz (INIBICA)
  6. 6Laboratory of Immunophenomics, School of Medical Technology, Xinxiang Medical University
Read full textPDFDOICite

Abstract

The tyrosine kinase ZAP-70 is essential for T-cell activation and development, but the mechanisms regulating its activity remain unclear. Previous studies showed that the Src-family kinase LCK binds phosphorylated tyrosine 319 of ZAP-70 via its SH2 domain. Additionally, a gain-of-function ZAP-70 mutation involving the YEEI motif enhances LCK recruitment and TCR-mediated signaling. To investigate the physiological consequences of enhanced ZAP-70-LCK interaction in vivo , we generated a knock-in mouse model expressing the Zap70 YEEI gain-of-function mutation. Analysis of thymocyte development revealed that the Zap70 YEEI mutation altered T-cell maturation, resulting in increased differentiation of thymic regulatory T (Treg) cells and reduced thymic negative selection. In the peripheral T-cell compartment, mutant mice exhibited decreased surface expression of the TCRαβ complex and an increased frequency of memory CD4 T cells. These findings indicate that enhancing the ZAP-70-LCK interaction modifies signaling thresholds during thymic selection and peripheral T-cell homeostasis. Collectively, our results demonstrate that a gain-of-function mutation in Zap70 significantly reshapes T-cell development and maturation, highlighting the importance of regulated ZAP-70-LCK interactions in establishing immune tolerance and maintaining T-cell compartment balance.

Related

  1. A hyper-IgM2 AID mutation limits IgH break formation but preserves affinity maturation
    Kalina T. Belcheva, Priyanka Chowdhury, Vivian L.S. Kuan +7
    Cell ReportsPeer-reviewedCC BY 4.0General biologyCrossref
  2. The VGLUT3-p.T8I Mutation Alters Striatal Acetylcholine Dynamics in Response to Social Stressors and Drives Selective Social Avoidance in Male Mice
    M. Pujol, V. Bernard, S. El Mestikawy +2
    bioRxivPreprintAll rights reservedFull textNeurosciencebioRxiv
  3. A novel A-to-G mutation in circBDP1 alters adipocyte proliferation and differentiation and affects bovine carcass traits
    Enhui Jiang, Chiyuan Zhang, Zhuoyuan He +7
    Journal of Zhejiang University SCIENCE BPeer-reviewedLicence not statedFull text9 citedGenetics & genomicsOpenAlex
  4. H3-K27M mutation alters the dynamics of human hematopoietic stem cells and delays erythroid differentiation
    M. Brunetti, H. Dakik, F. Beigmohammadi +2
    bioRxivPreprintCC BYFull textCell biologybioRxiv
  5. The CYFIP2 Arg87Cys Mutation Reshapes the Interactome and Alters Stress Fiber-Associated Proteins
    Ísis V. Biembengut, Emanuella de C. Andreassa, Marlon D. M. dos Santos +5
    ACS OmegaPeer-reviewedCC BY 4.0Full textGenetics & genomicsCrossrefEurope PMCEurope PMCPMC

Cite

BibTeXRIS
BibTeX
@article{vicobarranco2026zap70,
  title = {{A Zap70 gain-of-function mutation alters mouse thymic maturation}},
  author = {Inmaculada Vico-Barranco and Fanghui Zhang and Claude Grégoire and Luis M. Fernández-Aguilar and Mikel M. Arbulo-Echevarria and Isaac Narbona-Sánchez and Raquel Muñoz-Fernández and Bernard Malissen and Marie Malissen and Enrique Aguado},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1932213},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1932213/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A Zap70 gain-of-function mutation alters mouse thymic maturation
AU  - Inmaculada Vico-Barranco
AU  - Fanghui Zhang
AU  - Claude Grégoire
AU  - Luis M. Fernández-Aguilar
AU  - Mikel M. Arbulo-Echevarria
AU  - Isaac Narbona-Sánchez
AU  - Raquel Muñoz-Fernández
AU  - Bernard Malissen
AU  - Marie Malissen
AU  - Enrique Aguado
PY  - 2026
DA  - 2026/10/06
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1932213
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1932213/full
AB  - The tyrosine kinase ZAP-70 is essential for T-cell activation and development, but the mechanisms regulating its activity remain unclear. Previous studies showed that the Src-family kinase LCK binds phosphorylated tyrosine 319 of ZAP-70 via its SH2 domain. Additionally, a gain-of-function ZAP-70 mutation involving the YEEI motif enhances LCK recruitment and TCR-mediated signaling. To investigate the physiological consequences of enhanced ZAP-70-LCK interaction in vivo , we generated a knock-in mouse model expressing the Zap70 YEEI gain-of-function mutation. Analysis of thymocyte development revealed that the Zap70 YEEI mutation altered T-cell maturation, resulting in increased differentiation of thymic regulatory T (Treg) cells and reduced thymic negative selection. In the peripheral T-cell compartment, mutant mice exhibited decreased surface expression of the TCRαβ complex and an increased frequency of memory CD4 T cells. These findings indicate that enhancing the ZAP-70-LCK interaction modifies signaling thresholds during thymic selection and peripheral T-cell homeostasis. Collectively, our results demonstrate that a gain-of-function mutation in Zap70 significantly reshapes T-cell development and maturation, highlighting the importance of regulated ZAP-70-LCK interactions in establishing immune tolerance and maintaining T-cell compartment balance.
SN  - 1664-3224
ER  -