CD8 + T-cell development in the thymus generates a predominant population of conventional naive cells, along with minor populations of “innate” T cells that resemble memory cells. Recent studies analyzing a variety of KO or knock-in mice have indicated that impairments in the T-cell receptor (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 (Eomes). 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, IFN regulatory factor 4 (IRF4). IRF4 is up-regulated following TCR stimulation in WT T cells; further, this up-regulation is impaired in T cells treated with a small-molecule inhibitor of the Tec family tyrosine kinase, IL-2 inducible T-cell kinase (ITK). In contrast to WT cells, activation of IRF4-deficient CD8 + T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. In addition, inhibition of ITK together with IL-4 increases Eomeso up-regulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8 + T-cell activation and that this signaling pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8 + T cells.
In response to acute virus infections, CD8+ T cells differentiate to form a large population of short-lived effectors and a stable pool of long-lived memory cells. The characteristics of the CD8+ T cell response are influenced by TCR affinity, antigen dose, and the inflammatory cytokine milieu dictated by the infection. To address the mechanism by which differences in TCR signal strength could regulate CD8+ T cell differentiation, we investigated the transcription factor, IRF4. We show that IRF4 is transiently upregulated to differing levels in murine CD8+ T cells, based on the strength of TCR signaling. In turn, IRF4 controls the magnitude of the CD8+ T cell response to acute virus infection in a dose-dependent manner. Modest differences in IRF4 expression dramatically influence the numbers of short-lived effector cells at the peak of the infection, but have no impact on the kinetics of the infection or on the rate of T cell contraction. Further, the expression of key transcription factors such as TCF1 and Eomes are highly sensitive to graded levels of IRF4. In contrast, T-bet expression is less dependent on IRF4 levels, and is influenced by the nature of the infection. These data indicate that IRF4 is a key component that translates the strength of TCR signaling into a graded response of virus-specific CD8+ T cells.
SummaryTec family kinases are important components of antigen receptor signaling pathways in B cells, T cells, and mast cells. In T cells, three members of this family, Itk, Rlk, and Tec, are expressed. In the absence of Itk and Rlk, T-cell receptor signaling is impaired, with defects in mitogen-activated protein kinase activation, Ca 2+ mobilization, and actin polymerization. During T-cell development in the thymus, no role has been found for these kinases in the CD4 + versus CD8 + T-cell lineage decision; however, several studies indicate that Itk and Rlk contribute to the signaling leading to positive and negative selection. In addition, we and others have recently described an important role for Itk and Rlk in the development of conventional as opposed to innate CD4 + and CD8 + T cells. Natural killer T and γδ T-cell populations are also altered in Itk-and Rlk/Itk-deficient mice. These findings strongly suggest that the strength of T-cell receptor signaling during development determines whether T cells mature into conventional versus innate lymphocyte lineages. This lineage decision is also influenced by signaling via SLAM (signaling lymphocytic activation molecule) family receptors. Here we discuss these two signaling pathways that each contribute to conventional versus innate T-cell lineage commitment.
The E2F4 protein is involved in gene repression and cell cycle exit, and also has poorly understood effects in differentiation. We analyzed the impact of E2F4 deficiency on early steps in mouse hematopoietic development, and found defects in early hematopoietic progenitor cells that were propagated through common lymphoid precursors to the B and T lineages. In contrast, the defects in erythromyeloid precursor cells were self-correcting over time. This suggests that E2F4 is important in early stages of commitment to the lymphoid lineage. The E2F4-deficient progenitor cells showed reduced expression of several key lymphoid-lineage genes, and overexpression of two erythromyeloid lineage genes. However, we did not detect effects on cell proliferation. These findings emphasize the significance of E2F4 in controlling gene expression and cell fate.
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.
CD8+ T cells undergo rapid proliferation, differentiation and contraction following acute infections. One of the key factors influencing these CD8+ T cell responses is the strength of TCR-ligand interactions. We have previously shown that the transcription factor Interferon Regulatory Factor 4 (IRF4) is important in the differentiation of CD8 T cells. IRF4 is not expressed in naïve CD8 T cells, but is rapidly up-regulated upon T cell activation. Further, this up-regulation is directly regulated by the strength of TCR signaling, such that stronger signaling leads to higher levels of IRF4 expression. To test the function of IRF4 in vivo, we have utilized the acute LCMV infection model together with mice expressing graded levels of IRF4. These studies indicated that CD8 T cell proliferation and differentiation into effector and memory populations is regulated by IRF4. Further, we found that IRF4 was impacting the expression of major downstream transcription factors, Eomes, TBet, and TCF1, that are critical for effector responses and memory differentiation. Together these data establish a transcription factor network that is highly responsive to the strength of TCR-ligand interactions during infection.
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