A rat model carrying a nonsense mutation in Nfkb2 (c.2602T>A; p.Tyr867*, referred to as Nfkb2p.Tyr867*) exhibits pronounced changes in the thymic stroma. The mutation led to a reduction in K5+ medullary thymic epithelial cells and decreased expression of AIRE, a transcriptional regulator critical for central tolerance. These stromal defects indicate disruption of the niche that supports thymocyte selection and the establishment of self-tolerance.
The findings implicate the non-canonical NF-κB pathway, in which NFKB2 is central, as necessary for maintaining a functional medullary thymic epithelial cell compartment and appropriate levels of AIRE expression. The study reports these thymic microenvironmental changes as primary features in the mutant rat, reflecting mechanisms that may underlie autoimmune manifestations reported in humans with pathogenic NFKB2 variants.
Alterations in the thymic stroma in Nfkb2p.Tyr867* animals were accompanied by altered thymocyte development. The mutant animals displayed impaired development of thymic regulatory T (Treg) populations. Given the reduced AIRE expression and decreased K5+ medullary epithelial cells, the observed changes in thymocyte maturation and Treg output are consistent with defective central tolerance and thymic selection processes.
Impaired thymic Treg populations may contribute both to defective control of autoreactive T cells and to susceptibility to infections if peripheral regulatory mechanisms are compromised. The source reports these thymic Treg defects as a key component of the combined immunodeficiency phenotype associated with the Nfkb2 mutation.
Peripheral lymphoid organization was profoundly affected in the Nfkb2-mutant rats. Notably, the animals lacked lymph nodes, indicating a developmental failure of peripheral lymphoid organogenesis tied to defective non-canonical NF-κB signaling.
The spleen also showed structural defects, including abnormalities of the splenic marginal zone, which is a critical region for antigen capture and B-cell responses. Loss of normal peripheral lymphoid architecture is likely to have major consequences for antigen presentation, lymphocyte interactions, and initiation of adaptive immune responses.
T-cell compartments were altered in the periphery. Both CD4+ and CD8+ T-cell homeostasis were perturbed in the mutant rats. Within CD4+ populations, the study reports impaired regulatory T-cell populations recapitulating thymic deficits, and a reduction in ICOS expression on CD4+ T cells.
Reduced ICOS, a co-stimulatory molecule important for T-cell help to B cells and follicular helper T-cell function, suggests compromised T-cell support for humoral responses. These T-cell alterations likely contribute to the combined immunodeficiency phenotype by weakening both cellular immune responses and T-cell–dependent help for B-cell maturation.
The B-cell lineage was markedly disrupted in Nfkb2p.Tyr867* rats. The peripheral B-cell compartment showed accumulation of IgM+IgD- transitional cells and a pronounced reduction of IgD+ mature B cells. This pattern indicates a blockade or delay in B-cell maturation from transitional stages to fully mature naive B cells.
Given the roles of non-canonical NF-κB signaling in lymphoid organ structure and B-cell development, the observed B-cell maturation defects align with the peripheral lymphoid defects and altered T-cell help. The study highlights these B-cell abnormalities as central contributors to the animals’ impaired humoral immunity.
Consistent with disrupted B-cell development and impaired T-cell help, the Nfkb2-mutant rats exhibited profound humoral immune failure. The study reports a complete absence of circulating immunoglobulins in these animals.
This profound hypogammaglobulinemia demonstrates that the Nfkb2p.Tyr867* variant produces a systemic defect in antibody-mediated immunity. Coupled with thymic and peripheral lymphoid abnormalities, the lack of circulating immunoglobulins defines a combined immunodeficiency affecting both cellular and humoral arms of adaptive immunity.
Collectively, the reported observations define a systemic combined immunodeficiency phenotype in rats carrying the Nfkb2 p.Tyr867* mutation. The constellation of findings—thymic stromal defects with reduced K5+ medullary epithelial cells and decreased AIRE, impaired thymic and peripheral Treg populations, absence of lymph nodes, splenic marginal zone defects, disrupted T- and B-cell homeostasis, and complete absence of circulating immunoglobulins—supports a central role for non-canonical NF-κB signaling in organizing lymphoid tissues and enabling adaptive immunity.
The authors present this rat model as a tool for mechanistic studies into how pathogenic NFKB2 variants lead to combined immunodeficiency and CVID-like syndromes in humans. The model may be useful to dissect contributions of thymic versus peripheral defects to autoimmunity and infection susceptibility and to evaluate interventions that target pathways downstream of non-canonical NF-κB signaling.
Note: The source article provided descriptive and experimental observations; specific experimental methods, quantitative data, and therapeutic evaluations were not detailed in the text provided here.