The role of the zinc transporter ZIP7 in adaptive immunity

Thesis

The zinc transporter SLC39A7, or ZIP7, is critical for early B cell development, but its role in peripheral adaptive immunity remains incompletely defined. Since ZIP7 hypomorphic mutations preferentially affect B cells over T cells in humans and in murine models, we hypothesize that lymphocyte lineage-specific requirements and differential adaptive responses determine the varying phenotypic consequences of ZIP7 deficiency. This thesis investigates the impact of ZIP7 deficiency on B and T cell maintenance, function, and stress adaptation using a series of inducible and tissue-specific mouse models, complemented by single-cell transcriptomics.

Varying degrees of Ert2-cre-based ZIP7 deficiency revealed that ZIP7 is essential for maintaining immune cell populations during early development, including pro-B to immature B cells, and thymic late DN to DP T cells. Cr2-cre and Cd4-cre conditional knockout models also confirmed that marginal zone B and mature T cells exhibit intrinsic survival disadvantages under ZIP7 deficiency, especially in competitive settings. Functionally, ZIP7-deficient B cells failed to mount robust humoral responses to both T-independent and T-dependent antigens. Adoptive transfer models revealed inefficient recruitment and survival of B cells in germinal centres, highlighting a critical role for ZIP7 in sustaining B cell persistence during immune activation.

Single-cell RNA sequencing further uncovered a conserved stress signature marked by high Atf4 and Pck2, and low Eif2b expression, consistent with a split integrated stress response. While stress-marked T cells activated broader compensatory pathways, B cells mounted a more limited adaptive response, potentially contributing to their heightened vulnerability. Divergent mTORC1 activity further suggested lineage-specific compensatory strategies under ZIP7-induced stress.

Together, this work identifies ZIP7 as a non-redundant regulator of lymphocyte fitness under metabolic stress. It defines gene dosage-dependent thresholds of ZIP7 sufficiency across immune cell subsets and highlights transcriptional stress adaptation as a critical vulnerability in ZIP7-deficient cells—offering insights with potential translational relevance for primary immunodeficiencies.

Authors: Yan, J

• DOI: 10.5287/ora-jnm5omeyy
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: conditional knockout; SLC39A7; adaptive immunity; gene dosage effect; ZIP7; primary immunodeficiency diseases; single-cell gene expression analysis; ER stress; B cell development; T cell development; integrated stress response
• Subjects: Lymphocytes; Genetic disorders; Immunodeficiency; Molecular biology; Immunology