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The generation of naïve T lymphocytes is critical for immune function yet the mechanisms governing their maturation remain incompletely understood. We have identified a mouse mutant,  bloto , that harbors a hypomorphic mutation in the zinc finger protein Zfp335.  Zfp335  bloto/bloto  mice exhibit a naïve T cell deficiency due to an intrinsic developmental defect that begins to manifest in the thymus and continues into the periphery, affecting T cells that have recently undergone thymic egress. The effects of Zfp335 bloto  are multigenic and cannot be attributed to altered thymic selection, proliferation or Bcl2-dependent survival. Zfp335 binds to promoter regions via a consensus motif, and its target genes are enriched in categories related to protein metabolism, mitochondrial function, and transcriptional regulation. Restoring the expression of one target, Ankle2, partially rescues T cell maturation. These findings identify Zfp335 as a transcription factor and essential regulator of late-stage intrathymic and post-thymic T cell maturation.

Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment