Zfp281 and Zfp148 control CD4 + T cell thymic development and T H 2 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 _H 2) 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 _H 2 cytokine genes but not of the T _H 2 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 _H 2 cytokines. Thus, Zfp148 and Zfp281 collaborate with Gata3 to promote CD4 ⁺ T cell development and T _H 2 cell responses.