Zfp281 and Zfp148 control CD4⁺ T cell thymic development and T_H2 functions

How CD4⁺ lineage gene expression is initiated in differentiating thymocytes remains poorly understood. Here, we show that the paralog transcription factors Zfp281 and Zfp148 control both this process and cytokine expression by T helper cell type 2 (T_H2) effector cells. Genetic, single-cell, and spatial transcriptomic analyses showed that these factors promote the intrathymic CD4⁺ T cell differentiation of class II major histocompatibility complex (MHC II)-restricted thymocytes, including expression of the CD4⁺ lineage-committing factor Thpok. In peripheral T cells, Zfp281 and Zfp148 promoted chromatin opening at and expression of T_H2 cytokine genes but not of the T_H2 lineage-determining transcription factor Gata3. We found that Zfp281 interacts with Gata3 and is recruited to Gata3 genomic binding sites at loci encoding Thpok and T_H2 cytokines. Thus, Zfp148 and Zfp281 collaborate with Gata3 to promote CD4⁺ T cell development and T_H2 cell responses.