Partial loss of interleukin 2 receptor gamma function in pigs provides mechanistic insights for the study of human immunodeficiency syndrome

In this study, we described the phenotype of monoallelic interleukin 2 receptor gamma knockout (mIL2RG(+/Δ69-368) KO) pigs. Approximately 80% of mIL2RG(+/Δ69-368) KO pigs (8/10) were athymic, whereas 20% (2/10) presented a rudimentary thymus. The body weight of IL2RG(+/Δ69-368)KO pigs developed normally. Immunological analysis showed that mIL2RG(+/Δ69-368) KO pigs possessed CD25(+)CD44- or CD25-CD44(+) cells, whereas single (CD4 or CD8) or double (CD4/8) positive cells were lacking in mIL2RG(+/Δ69-368) KO pigs. CD3(+) cells in the thymus of mIL2RG(+/Δ69-368) KO pigs contained mainly CD44(+) cells and/or CD25(+) cells, which included FOXP3(+) cells. These observations demonstrated that T cells from mIL2RG(+/Δ69-368) KO pigs were able to develop to the DN3 stage, but failed to transition toward the DN4 stage. Whole-transcriptome analysis of thymus and spleen, and subsequent pathway analysis revealed that a subset of genes differentially expressed following the loss of IL2RG might be responsible for both impaired T-cell receptor and cytokine-mediated signalling. However, comparative analysis of two mIL2RG(+/Δ69-368) KO pigs revealed little variability in the down- and up-regulated gene sets. In conclusion, mIL2RG(+/Δ69-368) KO pigs presented a T-B+NK- SCID phenotype, suggesting that pigs can be used as a valuable and suitable biomedical model for human SCID research.