Graded Levels of IRF4 Regulate CD8+ T Cell Differentiation and Expansion, but Not Attrition, in Response to Acute Virus Infection

Abstract

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.

Cutting Edge: The Orphan Nuclear Receptor Nr4a1 Regulates CD8+ T Cell Expansion and Effector Function through Direct Repression of Irf4

“…It was reported previously that IRF4 sustains proliferation by repressing the production of CDK inhibitors and Bim (8,10,11,13), suggesting that elevated levels of IRF4 in Nr4a1-deficient CD8 + T cells function to repress these factors, which results in the increase in homeostatic proliferation. We showed previously that there was no difference in apoptosis between Nr4a1 2/2 and B6 mice (15) and confirmed this finding (Supplemental Fig.…”

“…IFN regulatory factor (IRF)4, a member of the IRF family of transcription factors, was recently shown to be vital for sustaining the expansion and effector differentiation of CD8 + T cells (8)(9)(10). IRF4-deficient CD8 T cells proliferated less, were more prone to apoptosis, and produced fewer effector molecules, such as IFN-g (11).…”

“…The ablation of Nr4a1 gene expression resulted in increased proliferation after stimulation. Previous studies determined that ectopic expression of IRF4 strongly promoted the expansion of OT1 CD8 T cells (8,10,11,13). We clearly demonstrate that the Nr4a1-deficient CD8 T cell population, which has increased expression of IRF4, exhibits faster rates of proliferation upon stimulation.…”

mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

“…2B, Sema4A 2/2 CD8 + cells did not exhibit higher levels of cell death. It is noteworthy that the expression of IRF4, which is required for expansion of CD8 + T cells and effector differentiation (41,50,51), was not affected in the absence of SEMA4A, suggesting that the activities of SEMA4A on CD8 + T cells are not dependent on IRF4. This finding suggests that IRF4-dependent signal transduction alone is not sufficient for CD8 + T cell differentiation, and SEMA4A-mediated signals are required in addition to these signals.…”

Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice

“…Currently, IRF4 is considered to be a key component that translates TCR affinity or the strength of TCR signalling into the functions of activated CD8 + T cells, including their differentiation and expansion in a dose-dependent manner [20,43]. Interestingly, this gene-dose effect was evident in IRF4-haploinsufficient CD8 + T cells.…”