Zarin P et al 2015

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Cellular Immunology 296 (2015) 70–75

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Gamma delta T-cell differentiation and effector function programming, TCR signal strength, when and how much? Payam Zarin, Edward L.Y. Chen, Tracy S.H. In, Michele K. Anderson, Juan Carlos Zúñiga-Pflücker ⇑ Department of Immunology, University of Toronto, and Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada

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Article history: Received 6 February 2015 Revised 18 March 2015 Accepted 20 March 2015 Available online 25 March 2015 Keywords: Gamma delta T cells T cell receptor Lineage commitment T cell development

a b s t r a c t cd T-cells boast an impressive functional repertoire that can paint them as either champions or villains depending on the environmental and immunological cues. Understanding the function of the various effector cd subsets necessitates tracing the developmental program of these subsets, including the point of lineage bifurcation from ab T-cells. Here, we review the importance of signals from the T-cell receptor (TCR) in determining ab versus cd lineage fate, and further discuss how the molecular components of this pathway may influence the developmental programming of cd T-cells functional subsets. Additionally, we discuss the role of temporal windows in restricting the development of IL-17 producing cd T-cell subtypes, and explore whether fetal and adult hematopoietic progenitors maintain the same potential for giving rise to this important subset. Ó 2015 Elsevier Inc. All rights reserved.

1. Introduction Since their serendipitous discovery some thirty years ago, cd Tcells have emerged as an evolutionarily conserved lymphocyte subset with great functional range, varying based on the species, tissue, and immunological milieu [1–7]. The differential contribution to immunity by these cells is best illustrated by their variable abundance based on species and disease state. To this end, cd T-cells can comprise between 60–80% of circulating CD3+ cells in livestock such as cattle, pigs, and sheep [8], and in humans cd T-cells can rise from 2% to 60% of total CD3+ lymphocytes based on the immunological challenge [9]. In mice, cd T-cells are shown to play a role in pathogen clearance, tissue repair, tumor surveillance, and immunoregulation, as well as in autoimmunity, allergy and carcinogenesis [4,6,10–12]. Perhaps the best-studied tissue that displays the contribution of cd T-cells to both health and disease is the skin. To this end, cd Tcells are known to be key players in down-regulating inflammation and mediating wound repair in the skin [11,13–15] but have also been shown to exacerbate disease under different conditions such as experimentally-induced psoriasis, in which diminished accumulation of IL-17-producing cd T-cells (cd17) in the skin results in a decrease in inflammatory symptoms [16–19]. Further deleterious contributions of cd T-cells is observed in models of ischemic brain injury, experimental autoimmune encephalomyelitis (EAE), and collagen induced arthritis (CIA), where cd17 cells are ⇑ Corresponding author. E-mail address: [email protected] (J.C. Zúñiga-Pflücker). http://dx.doi.org/10.1016/j.cellimm.2015.03.007 0008-8749/Ó 2015 Elsevier Inc. All rights reserved.

known to be major contributors of inflammation and associated disease pathology [20–24]. In addition to contributing to autoimmunity, cd T-cells can also be deleterious in some models of breast and ovarian cancers, as their contribution to the inflammatory milieu and recruitment of other immune cells (such as small peritoneal macrophages in an ovarian cancer model), works directly against cancer immunosurveillance [25,26]. Conversely, immune regulation by lung resident cd T-cells is crucial for down regulating inflammation and inducing tissue repair in different models of infection or stress induced emphysema [27–29]. Finally, there exists extensive evidence of cd17 involvement in mounting an effective immune response against pathogens including Staphylococcal aureus, Listeria monocytogenes, Escherichia coli, Bacillus subtilis, and Mycobacterium tuberculosis [20,30–34]. Thus, it is clear cd T-cells can serve as important players in both immunity and tissue homeostasis, but also contribute to immune dysfunction and inflammatory pathogenesis. With this in mind, it is important to better understand how cd T-cells are first generated and how their differentiation within the thymus affects their final effector function. 1.1. A role for T cell receptor (TCR) signals in ab versus cd lineage fate Both cd and ab T-cells develop from a bipotent progenitor in the thymus following a process that involves the rearrangement of their namesake receptors through V(D)J recombination [35,36]. In the mouse thymus, these CD4 , CD8 double negative (DN) progenitors first progress from a DN2 (CD44+ CD25+) towards a DN3 (CD44 CD25+) stage of development while undergoing events that

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lead to cd or ab lineage fate determination. Early explanations of the divergent development of these cells arose from an observation that cd T-cells appeared in the mouse thymus prior to ab T-cells, hence suggesting that the progenitor was poised to preferentially give rise to a cd T-cell [37]. This timing dependent or stochastic model was directly opposed by the discovery of a c gene silencer that resulted in normal ab T-cell frequencies in cd T-cell transgenic mice [38]. As the absence of this silencer led to reduced ab T-cell frequencies, a second instructional model was proposed whereby the uninhibited expression of cd TCR or pre-TCR (pTa/TCRb) would directly result in development along the cd or ab lineage [38,39]. Subsequent studies investigating this theory at a single cell level showed that DN3 progenitors expressing pre-TCR or cd TCR retained the potential to progress towards either lineage, hence discounting the original instructional model [35,40]. These findings among others lend direct support to a quantitative signal strength model, whereby the amount of signal accumulated downstream of the TCR would drive the differentiation of progenitors along either lineage [36,41–43]. More specifically, the model suggests that a strong cd TCR signal would result in higher activation of the ERK-MAPK pathway, leading to a higher induction of the Early Growth Response (EGR1, EGR3) transcription factors and their target Inhibitor of DNA binding 3 (Id3) [44–46]. Id proteins are direct inhibitors of E2A, a helix-loop-helix protein, which serves an important role in thymocyte development as a checkpoint regulator [47]. As proposed by the signal strength hypothesis, the higher accumulation of Id3 results in stronger inhibition of E2A, and thus expression of cd T-cell hallmark genes. Conversely, weaker signals through the Notch receptors and pre-TCR would result in more modest accumulation of Id3, and hence weaker inhibition of E2A leading to further development along the ab lineage [36]. Although it has been proposed that in some instances, the simple expression of the cd TCR is sufficient to initiate the differentiation signals [48,49], more recent work by our group and others points the possibility of an active role for the cd TCR – ligand interaction during the development of at least some subsets with known ligands [40,50]. Studies making use of RAG2 / progenitors transduced with the transgenic KN6 cd TCR suggest bipotency based on the strength of ligand engagement for DN3 progenitors expressing the same cd TCR. KN6 is an example of a cd T-cell that specifically binds non-classical MHC-I like molecules such that include T10 and T22 [51–53]. More specifically, following interaction with TCR weak ligand T10, a fair proportion of the transgenic KN6 cd T-cells were shown to develop towards the ab lineage, whereas provision of a strong T22 ligand, resulted in a higher proportion of cells maturing as DN, CD24lo, CD73hi cd T-cells [50]. In what can be deemed as further proof for a cumulative signal strength hypothesis, KN6 cd T-cells that also expressed pre-TCR, were more adept at maturing along the cd T-cell lineage when presented with T10, in comparison to progenitors only expressing the cd TCR, suggesting that the signals through both the cd and preTCR combine to deliver a stronger signal [50]. It can therefore be concluded that differences in signal strength dictate ab versus cd lineage choice through modulation of lineage specific transcription factors. It is then also likely that within these distinct lineages, the graded signals downstream of each TCR results in differential regulation of transcription factors essential for the functional maturation of effector subtypes (Fig. 1). 1.2. TCR signal strength model extended: role in functional development

cd T-cells are largely associated with the innate arm of the immune system thanks to their rapid cytokine response and their preferred persistence in mucosal tissues. While this association

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has often called into question the functionality of the cd TCR, recent findings provide support for the relevance of ligand engagement in the functional maturation and activity of at least a group of these cells. Among other works, this is supported by evidence showing that differential signal accumulation downstream of the TCR can directly affect IFNc production by in vitro-derived KN6 cd T-cells [50]. This association is further supported by earlier publications that show Id3 induction is required for cytokine secretion, lineage specific gene expression, and overall functional competence of several cd T-cell subtypes. Arguably, the most widely accepted and clear surface marker to delineate cd T-cell cytokine profile in both mouse and human subsets has been the TNF superfamily member CD27, with CD27hi cells representing IFNc producers, and CD27lo cells containing the cd17 T-cell subsets [54–57]. Although the low expression of this marker is commonly associated with antigen naïve cells, cd T-cells that express IL-17 following TCR engagement of the model antigen phycoerythrin (PE), are found to be CD27 CD44+ CD62lo, hence necessitating further clarification of the link between CD27 expression, TCR signals, and cytokine production [58,59]. More recently, Wencker et al. showed that dampening of the cd TCR signaling components led to a near depletion of the CD27 cd17 population in both adult and neonates, insinuating that the cd TCR is at the very least essential to the development, if not effector function, of the cd17 subset [60]. These findings are contradictory to earlier work by Jensen et al., who analyzed T22-tetramer binding cd Tcells from wild type or b2m / (MHC-Ib ligand deficient) mice, and concluded that only antigen-naïve T22-tetramer binding cd T-cells from b2m / mice were able to produce IL-17, whereas antigen-experienced cd T-cells produced IFNc [61]. While this work further suggests the importance of cd TCR signal strength in determining functional differentiation for IFNc producing cd T-cells, it does not rule out the possibility of other environmental cues leading to the differentiation of cd17 cells in the abnormal b2m / thymic environment. Therefore, a controlled system whereby the binding strength of the cd TCR ligand can be directly modulated and measured would serve as an ideal model for understanding the role of the cd TCR in determining their functional differentiation. This system would also help elucidate the role of cd TCR signal strength in IL-4 production, a topic for which most of the current literature focuses on NKT like cd T-cell subsets that paradoxically require TCR cross-linking but not Id3 expression for IL-4 production [62,63]. While one means of achieving this is using the KN6 transgenic model for which a weak and strong ligand have been defined, another method may involve mutating the CDR3 region of a cd TCR with a known ligand, and assessing effector maturation as a function of binding affinity. These experiments will be important in defining a mechanism of how differential TCR signals are translated and integrated into the effector programming of cd T-cell subsets. 1.3. E proteins and Id factors in cd T-cell development The transcriptional programs that enable cd T-cells to recognize pathogens and respond to them in a context-specific manner are set during intrathymic development, resulting in the generation of IFNc or IL-17 producing cd T cells. These functional programs can be linked to expression of different Vc TCR chains. The transcription factors Sox13 and RORct (Rorc) are essential for IL-17 producing cd T-cells, including Vc6+ and some Vc4+ T cells, while Eomes and Tbet are hallmarks of IFNc producing subtypes, such as Vc5+ dendritic epidermal T-cells [20,64,65]. A recent study showed that thymic mature Vc4+ T cells from Sox13-deficient mice exhibit a block in IL-17 production and RORct expression [65], suggesting that Sox13 is upstream of RORct in the gene network that drives IL-17 expression. However, despite recent studies that

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Fig. 1. Model for TCR signal strength in determining ab versus cd lineage commitment, and effector function differentiation. Final bifurcation of ab and cd lineages occurs at the DN3 stage of T-cell development. DN3 cells that have rearranged a functional TCRb chain receive weak pre-TCR signals (b-selection) and become CD4+ CD8+ ab lineage cells. Following successful TCRa chain rearrangement and positive selection, increasing strength of ab TCR signals affects the differentiation outcomes of CD8+, CD4+, NKT, and Treg cells. Conversely, DN3 cells that have rearranged functional c and d chains receive strong TCR signals to undergo cd-selection and remain CD4 CD8 cells. Increasing strength of the cd TCR signals dictate different effector function outcomes, with weaker signals inducing IL-17 production, stronger signals inducing IFNc, and even stronger signals inducing IL-4.

provided insights into the transcriptional network that drives installment of functional programs in cd T-cell subsets [65–67], there is still much to be understood. Current models suggest that interplay of Notch signals and TCR signals drives development as well as functional programming of cd T-cells. Specifically, a combination of strong Notch signals and weak TCR signals leads to the development of IL-17 producing cells, whereas strong TCR signals result in the development of IFNc producing cd T-cells [68–70]. One of the results of strong TCR signaling is the activation of RAS-ERK-MAP kinase cascade, which ultimately leads to up-regulation of Id3, which then acts as the dominant negative inhibitor of the activity of E proteins E2A, HEBCan and HEBAlt [71]. E protein activity is necessary to turn on RORct, a master regulator of IL-17 production in ab lineage Th17 cells, and may be involved in cd T-cell RORct regulation as well [72]. Furthermore, recent studies have provided evidence that E proteins and Id factors are involved in directing precursors towards expression of certain Vc chains and functional phenotypes associated with them [73]. Specifically, temporal rearrangement of TCRc genes during fetal and adult life has been shown to be regulated by E2A and Id factors [46,74]. E2A deficient mice have decreased Vc4 and increased Vc5 gene arrangement in adult thymus, suggesting that E2A activates Vc4 rearrangement and inhibits Vc5 rearrangement during adult life [74]. Id3 deficient mice, by contrast, have an increased number of Vc1+ T-cells, which are double producers of IFNc and IL-4 [46]. These studies together suggest that E proteins may play a role in directing precursors towards IL17 producing cd T-cells and Id factors in driving them towards IFNc producers both by directing TCR expression and by modulating the evens that occur downstream of the TCR signals. Therefore, studies that directly investigate the role of E proteins and Id factors in functional programming of cd T-cells will provide further insights into the complex network of TCR signaling and transcription factors that allow these cells to acquire and exert their functions.

2. Restricted temporal developmental of cd17 T-cells?

cd T-cells with associated Vc usages develop in coordinated waves beginning from fetal life. In mice, Vc5+ cells constitute the first wave, arising from approximately embryonic day 12 (E12) to E16, followed by Vc6+ cells from E14 to birth, Vc4+ cells from E16 onward, and Vc1+ cells from E18 onward [75]. The tissue and functional specificities associated with these Vc subsets, potentiates the theory that functional subsets of cd T cells similarly develop in coordinated waves during fetal life. First to arrive are

CD27+ CD45RB+ innate-like dendritic epidermal T cells (DETCs), followed by IL-17 producers that comprise both Vc6 and Vc4 subsets, IFNc producers that comprise both Vc4 and Vc1 subsets, and NKT-like cells that can produce IL-4 within a subset of the Vc1 compartment [76]. Studies of the temporal regulation of cd17 cells suggest that their generation is restricted to a window of opportunity during in utero life. Work by Haas et al. has demonstrated that reconstitution of lethally irradiated Il17af / adult or neonatal mice with bone marrow from TcrdH2BeGFP mice resulted in a failure to generate cd17 cells [77]. In addition, using Indu-Rag1 mice, in which induction of Rag1 expression and T cell development can be achieved via tamoxifen gavage, the group further showed that in this system, cd17 cells were not generated de novo in adult life [77]. There exists some controversy surrounding the strict requirement for an embryonic thymus to generate cd T-cells with a functional capacity for IL-17 production. A study by Gray et al. showed that transfer of WT bone marrow into lethally irradiated TCRd-deficient adult mice can reconstitute Vc4+ CCR6+ cells in lymph nodes and the dermis (CCR6 being a marker expressed by cd17 cells). However, it was noted that reconstitution was variable at 8 weeks post transfer, whereas at 12 weeks or more, it was more consistent [78]. The authors suggest that generation of adult cd17 cells may require stringent conditions that are undefined, implying that the development of cd17 cells may not ‘‘require’’ an embryonic thymus per se. Haas et al. showed that in uninduced Indu-Rag1 mice, there exist Thy1+ Sca1+ CCR6+ innate lymphoid cells (ILCs) that produce IL-17 in the adult thymus. It is proposed that the IL-17 produced by the ILCs negatively regulates the development of cd17 cells [77]. Therefore the embryonic thymus may provide a more favorable environment for cd17 cells to develop, as they are not subjected to the IL-17-mediated inhibition they would experience in the adult thymus. Returning to a stochastic model of development for cd T-cells, it is relevant to ask whether the progenitors from fetal or adult mice possess an equivalent capacity to give rise to cd17 cells if the putative inhibition in the adult thymic environment is removed. To this end, hematopoietic progenitor cells (HPCs) were enriched from E14 fetal liver or adult bone marrow of Rag2 / mice, and co-cultured with OP9-DL4 cells to induce T cell differentiation up to the DN3 (CD44 CD25+) stage (Fig. 2A). Both sets of progenitors were then transduced to express the KN6 cd TCR and allowed to further mature on OP9-DL4 cells for 4 days prior to harvesting and stimulation. Interestingly, we observed that KN6 cd T-cells, derived in vitro either from adult or fetal progenitors, possessed a nearly identical capacity to give rise to cd17 cells as determined by flow cytometric analysis

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A

B

Fig. 2. Testing whether the developmental stage of hematopoietic progenitors affects the generation of IL-17 producing cd T-cells in vitro. (A) Experimental approach, RAG2 / E14 fetal liver or 8 week old adult bone marrow hematopoietic progenitor cells (HPCs) were co-cultured on OP9-DL4 cells to induce T-cell development in vitro. After 7 days, cells were cultured on retroviral packaging cells (GP + E) for 24 h for transduction of the KN6 cd TCR. Sorted DN3 (CD44 CD25+) KN6+ (GFP+) cells (as shown) were recultured on OP9-DL4 for 4 days. The cells were then harvested and stimulated with PMA and ionomycin for 24 h, and IL-17 production was detected by intracellular staining using flow cytometry. (B) KN6+ cd T-cells derived from both fetal liver and adult bone marrow HPCs were able to give rise to IL-17 producing cells, as determined by intracellular IL-17 staining of KN6+ cd T-cells stimulated with PMA and ionomycin (left panels) or unstimulated (right panels), the cells were also analyzed for the expression of CD45, as indicated.

(Fig. 2B), and quantification by enzyme-linked immunosorbent assay (ELISA, data not shown). Thus, these results indicate that cd17 cells can indeed develop from adult progenitors when provided with the same environment as their fetal counterparts, making it unlikely that epigenetics play a role in the development of cd17 cells. A recent model to explain the development of cd17 cells suggests that there exists a ‘‘natural’’ and an ‘‘inducible’’ subset of cells [79]. In this model, natural, innate-like cd17 cells are exclusively developed in utero and are thought to be pre-programmed for IL17 production. These cells express IL-1 and IL-23 receptors, giving them the ability to respond to innate sources of these cytokines to initiate a rapid IL-17 response without necessitating additional TCR signaling. Conversely, inducible cd17 cells can develop postnatally in the neonatal or adult thymus, and behave more similarly to conventional Th17 cells in that they can exit the thymus as naïve, uncommitted cells. In the periphery, these inducible cells recognize antigen to gain IL-17 effector function, and upon antigen recognition up-regulate IL-1 and IL-23 receptors to induce IL-17 production in response to these cytokines [6,79]. One such example of these inducible cd17 cells may be the PE specific cd T-cells discussed earlier. Prior to immunization, the majority of PE-specific cd T-cells displayed a CD44 CD62L+ naive phenotype, which is in contrast to the CD44+ CD62L activated phenotype associated with cd17 cells. However, after PE immunization, the percentage of

CD44+ CD62L cells increased, and these activated cells act as effective producers of IL-17 [58]. 3. Concluding remarks In sum, it can be said that effective functional differentiation of

cd T-cells is fine-tuned by the integration of signals from the cdTCR, and those arising from other environmental cues, such as cytokine and Notch receptor signals. Noting that the functional differentiation of these cells is the product of multiple environmental and intrinsic cues, which are in turn potentially under temporal control, an in vitro system enables an ideal setting where the function of individual contributors of effector programming can be teased apart. This knowledge would then be critical for understanding how cd T-cell functions are regulated in health and disease. Acknowledgments We are thankful to Dr. Geneve Awong for her expert flow cytometry assistance. This work was supported by the Canadian Institutes of Health Research (MOP# 42387) and the National Institutes of Health Grant P01AI102853. JCZP is supported by a Canada Research Chair in Developmental Immunology. PZ is supported by an Ontario Graduate Scholarship.

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