Transcriptional regulation of effector and memory CD8+ T cell fates
Introduction
CD8+ T cells play a critical role in the immune responses to both intracellular pathogens and cancer [1, 2]. Upon pathogen-antigen or tumor-antigen stimulation, naïve CD8+ T cells (TN) undergo a massive clonal expansion to generate large numbers of effector T cells capable of eliminating cells bearing the target antigen. At the end of the primary response the majority of responding CD8+ T cells will undergo apoptosis; however, a small fraction of activated cells will persist long-term establishing a memory T cell population [3]. Expression of killer cell lectin-like receptor G1 (KLRG1) and IL-7 receptor-α (IL-7Rα) on responding CD8+ T cells can distinguish cells that are destined to die or survive as long-lived memory cells. Specifically, IL-7Rα+KLRG1− CD8+ T cells have a greater potential to enter into the memory pool, whereas IL-7Rα−KLRG1+ CD8+ T cells represent terminally differentiated, short-lived effector T cells (SLEC) [4]. The transcriptional regulation of these cell-fate decisions has undergone much scrutiny over the past years. Early studies establishing the transcriptional regulators Eomesodermin (EOMES), T-BET (encoded by T-BOX 21), B-cell CLL/lymphoma 6 (BCL-6) and B lymphocyte induced maturation protein 1 (BLIMP-1, encoded by PRDM1) as critical determinants of CD8+ T cell differentiation have been reviewed in detail elsewhere [5, 6]. Here, we discuss more recent advances that have shaped our understanding of the signaling pathways and transcriptional programs that regulate the formation of effector and memory CD8+ T cells.
Section snippets
STAT signaling
Signal transducer and activator of transcription (STAT) signaling pathways are central to the differentiation and long-term survival of CD8+ T cells. Seven members of the STAT family have been described in mammals (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6) [7]. While a single cytokine receptor can activate downstream multiple STATs, most receptors function through a dominant STAT protein. For instance, interleukin (IL)-6, IL-10 and IL-21 preferentially act through STAT3 while IL-12
WNT–β-catenin signaling
WNT–β-catenin signaling has recently emerged as a critical determinant of CD8+ T cell differentiation. This signaling pathway revolves around β-catenin which in the absence of WNT signals is targeted for proteasomal degradation by a ‘destruction complex’ consisting of Axin, Adenomatosis Polyposis Coli (APC), and the serine/threonine kinases Casein Kinase 1 (CK1) and Glycogen-Synthase Kinase 3β (GSK-3β) [23]. Binding of WNT to the Frizzled receptor and LRP5 or 6 co-receptors triggers a signaling
ID proteins
ID proteins are a key family of transcription regulators that control effector and memory CD8+ T cell development. These proteins, which lack a basic DNA-binding region, mainly function as negative regulators of E protein transcriptional activity by forming heterodimer through a helix–loop–helix (HLH) domain and preventing E proteins from binding to DNA [37]. Four ID proteins (ID1–ID4) have been described, but only the function of ID2 and ID3 has been investigated in the differentiation of
PI3K–AKT–mTOR signaling pathway
The nutrient-sensing serine/threonine protein kinase mammalian target of rapamycin (mTOR) is a well-established regulator of cell growth and metabolism, but more recently has emerged as a pivotal modulator of CD8+ T cell fate decisions. mTOR integrates signals from pro-inflammatory cytokines such as IL-2 and IL-12 through phosphoinositol 3-kinase (PI3K)–AKT signaling as well as WNT proteins via GSK-3β (Figure 1). Sustained activation of AKT/mTOR activity by IL-12 [43], expression of a
The Hippo signaling pathway
The Hippo pathway is an evolutionarily conserved intracellular signal transduction cascade that transduces cell–cell contact signals to trigger differentiation [53]. Recently this signaling pathway has also been demonstrated to affect the transcriptional regulation of differentiation of CD8+ T cells. The core components of this serine/threonine kinase pathway consists of Mammalian sterile-20-like kinase (MST), MOB kinase activator (MOB), Salvador homolog 1 (SAV1) and Large tumor suppressor
Concluding remarks
Over the past decade our understanding of the signaling pathways and transcriptional programs that control effector and memory CD8+ T cell fates has advanced considerably. It is becoming increasingly appreciated that between pathways regulating self-renewal and effector differentiation exist a significant amount of cross-talk such that the net influence of each pathways is finely balanced and tuned. For example, observations in other systems have demonstrated links between WNT and mTOR [63],
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by the Intramural Research Programs of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research, the Ludwig Institute for Cancer Research, the NIHR Cambridge Biomedical Research Centre and the Wellcome Trust. The authors would like to thank Y. Ji, C.A. Klebanoff and J. Crompton for helpful discussion.
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