Insufficient interleukin-12 signalling favours differentiation of human CD4⁺ and CD8⁺ T cells into GATA-3⁺ and GATA-3⁺ T-bet⁺ subsets in humanized mice

Summary: Differentiation of CD4⁺ T cells into type 1 or type 2 subsets is mediated by the expression of the opposing lineage defining transcription factors T-bet and GATA-3. However, the existence of GATA-3⁺ T-bet⁺ CD4⁺ T cells in mice suggests functional plasticity of these subsets. Little is known about type 1 and type 2 plasticity of human T-cell subsets in vivo. Here, we show that in the xenogeneic environment of humanized mice, which lacks a functional immune-regulatory network, human CD4⁺ and, notably, CD8⁺ T cells preferentially differentiate into interleukin (IL)-4⁺ GATA-3⁺ and IL-4⁺ interferon-γ⁺ GATA-3⁺ T-bet⁺ subsets. Treatment with recombinant human IL-12 or expansion of IL-12-producing human dendritic cells in vivo reverted this phenotype and led to the down-regulation of GATA-3 expression. These changes also correlated with improved antiviral immune responses in humanized mice. In conclusion, our study shows the capacity of human CD4⁺ and CD8⁺ T cells for stable co-expression of GATA-3 and T-bet in humanized mice and reveals a critical role for IL-12 in regulating this phenotype.