Abstract

Abstract CD8+ T cell development in the thymus generates a predominant population of conventional naïve cells, along with minor populations of ‘innate’ T cells that resemble memory cells. Recent studies analyzing a variety of knockout or knock-in mice have indicated that impairments in the TCR signaling pathway produce increased numbers of innate CD8+ T cells, characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor Eomesodermin. One component of this altered development is a non-CD8+ T cell-intrinsic role for IL-4. To determine whether reduced TCR signaling within the CD8+ T cells might also contribute to this pathway, we investigated the role of the transcription factor IRF4. IRF4 is upregulated following TCR stimulation in wild-type T cells; however, this upregulation is impaired in Itk-/- T cells, which have reduced responses to TCR signaling. Further, analysis of IRF4-deficient CD8+ thymocytes showed normal development of thymic CD8+ T cells. Interestingly, IRF4-deficient peripheral CD8+ T cells acquired a memory phenotype and expressed the transcription factor Eomesodermin. We also show that activation of naïve IRF4-deficient CD8+ T cells leads to rapid and robust expression of Eomesodermin. Together, these data indicate that IRF4 upregulation following CD8+ T cell activation normally suppresses Eomesodermin expression, thereby regulating the differentiation pathway of CD8+ effector T cells.

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