Immunology – DiGeorge's syndrome is characterized by congenital absence or severe hypoplasia of the thymus (T-cell deficiency). Which mouse model most closely mimics this human condition for experimental study?

Introduction:
DiGeorge's syndrome (22q11.2 deletion syndrome) classically involves thymic aplasia or hypoplasia, leading to profound T-cell immunodeficiency. To study T-cell–dependent immunity, researchers often turn to mouse models that reproduce an absent or nonfunctional thymus. This question asks which mouse strain most faithfully mirrors the thymic defect of DiGeorge's syndrome.

Given Data / Assumptions:

• DiGeorge's syndrome presents with absent/underdeveloped thymus and reduced mature T cells.
• Mouse strains differ in the specific immune components that are defective.
• We want the closest phenotypic match for thymic absence and T-cell deficiency.

Concept / Approach:
The nude mouse carries a Foxn1 mutation causing athymia (no thymic epithelium), resulting in a severe quantitative and functional deficit of T cells, while leaving B cells largely present but lacking T-cell help. This mirrors the thymic abnormality in DiGeorge's. By contrast, RAG-1/2 knockout mice cannot perform V(D)J recombination and therefore lack both T and B cells, which is broader than the typical DiGeorge profile. CD3 alterations affect TCR signaling rather than thymus development per se.

Step-by-Step Solution:

Verification / Alternative check:
Phenotyping of nude mice shows near absence of mature peripheral T cells with intact B-cell development but impaired T-dependent responses, paralleling thymic aplasia syndromes. Adoptive thymic transplantation rescues T-cell development, confirming the thymus-centric defect.

Why Other Options Are Wrong:

• Knockout mouse lacking RAG-1 and RAG-2: abolishes both T and B lymphocytes; not specific to thymus.
• “Mouse without a thymus”: vague, not a standard defined model; lacks mechanistic similarity.
• Recombinant mouse altering CD3: affects signaling; does not inherently remove the thymus.
• Severe macrophage-deficient mouse: defects are innate, not thymus/T-cell development.

Common Pitfalls:
Equating global lymphopenia (RAG KO) with thymic aplasia, or assuming any T-cell signaling defect models thymus absence.

Final Answer:
Nude (athymic) mouse with Foxn1 mutation