New roles for cyclin-dependent kinases in T cell biology: linking cell division and differentiation

Abstract

The proliferation of a few antigen-reactive lymphocytes into a large population of effector cells is a fundamental property of adaptive immunity. The cell division that fuels this process is driven by signals from antigen, co-stimulatory molecules and growth factor receptors, and is controlled by the cyclin-dependent kinase (CDK) cascade. In this Opinion article, we discuss how the CDK cascade provides one potential link between cell division and differentiation through the phosphorylation of immunologically relevant transcription factors, and how components of this pathway might ultimately participate in the decision between tolerance and immunity.

Figure 1 |. Regulation of T cell development and differentiation by members of the CDK family.

The figure shows the role of cyclin-dependent kinases (CDKs) and CDK inhibitors in the positive and negative regulation of T cell proliferation and cell fate decisions during thymic development, tolerance induction, effector differentiation, contraction and memory formation, and restimulation (secondary effector phase). DN, double negative; CTL, cytotoxic T lymphocyte; DP, double positive; FOXP3, Forkhead box P3; IFNγ, interferon-γ; IL-2, interleukin-2; SP, single positive; TReg cell, regulatory T cell.

Figure 2 |. Models to link cell cycle progression with T cell differentiation.

Differentiation might be influenced by cell cycle-dependent epigenetic changes, the unequal (asymmetric) segregation of effector molecules between daughter cells during mitosis or, as we propose in this Opinion article, the direct regulation of transcription factors by cyclin-dependent kinases (CDKs). CBP/p300, CREB-binding protein; FOXP3, Forkhead box P3; SP1; transcription factor SP1; STATs, signal transducers and activators of transcription.

Figure 3 |. Regulation of the regulatory T cell programme by CDK2 and p27.

The receptors for antigen, transforming growth factor-β (TGFβ) and interleukin-2 (IL-2) cooperate to induce expression of p27 (encoded by CDKN1B) and Forkhead box P3 (FOXP3) via transcription factors such as nuclear factor of activated T cells (NFAT), SMAD3, signal transducer and activator of transcription 5 (STAT5) and FOXO1. Concomitant activation of AKT and cyclin-dependent kinase 2 (CDK2), which inhibit the functions of SMAD3 and FOXO1, is opposed by PHLPP1 (an AKT phosphatase) and p27. This in turn protects FOXP3 from CDK2-mediated destabilization. JAK3, Janus kinase 3; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; TCR, T cell receptor; T_Reg cell, regulatory T cell. Both positive and negative roles for CDK2 in FOXO1 function have been described (represented by a question mark). Dashed arrows indicate shuttling between the nucleus and the cytosol.