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Memory Th1/Th2 Cell Generation Controlled by Schnurri-2

* and .

* Corresponding Author: Toshinori Nakayama—Department of Immunology (H3), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670 Japan. Email: pj.u-abihc.ytlucaf@amayakant

Memory T-Cells, edited by Maurizio Zanetti.
©2009 Landes Bioscience.
Read this chapter in the Madame Curie Bioscience Database here.

Schnurri (Shn) is a large zinc-finger containing protein, which plays a critical role in cell growth, signal transduction and lymphocyte development. There are three orthologues (Shn-1, Shn-2 and Shn-3) in vertebrates. In Shn-2-deficient mice, the activation of NF-κB in CD4 T-cells is upregulated and their ability to differentiate into Th2 cells is enhanced in part through the increased expression of GATA3. Shn-2 is found to compete with p50 NF-κB for binding to a consensus NF-κB motif and inhibit the NF-κB-driven promoter activity. In addition, Th2-driven allergic airway inflammation was enhanced in Shn-2-deficient mice. Therefore, Shn-2 appears to negatively control the differentiation of Th2 cells and Th2 responses through the repression of NF-κB function. Memory Th1/Th2 cells are not properly generated from Shn-2-deficient effector Th1/Th2 cells. The expression levels of CD69 and the number of apoptotic cells are selectively increased in Shn-2-deficient Th1/Th2 cells when they are transferred into syngeneic host animals, in which memory Th1/Th2 cells are generated within a month. In addition, an increased susceptibility to apoptotic cell death is also observed in vitro accompanied with the increased expression of FasL, one of the NF-κB-dependent genes. Th2 effector cells overexpressing the p65 subunit of NF-κB demonstrate a decreased cell survival particularly in the lymph node. These results indicate that Shn-2-mediated repression of NF-κB is required for cell survival and the successful generation of memory Th1/Th2 cells. This may point to the possibility that after antigen clearance the recovery of the quiescent state in effector Th cells is required for the generation of memory Th cells. A repressor molecule Shn-2 plays an important role in this process.

Introduction

The effector helper T (Th) cells can be categorized into at least three subsets in function, Th1, Th2 and Th17 cells. Th1 cells produce IFNγ and direct cell-mediated immunity. Th2 cells produce IL-4, IL-5 and IL-13 and play critical roles in allergic reactions. Th17 cells are involved in certain autoimmune diseases. The differentiation and the function of these Th cell subsets are governed by several critical transcription factors. Among them, GATA3 appears to be a master transcription factor for Th2 cell differentiation,1,2 T-bet for Th13 and RORγt for Th17.4

The generation of memory T-cells is crucial for adaptive immunity and protection from infectious disease upon subsequent exposure to pathogens. Figure 1 illustrates the cellular processes that are required for the generation of functional memory Th1/Th2 cells.5 Upon antigen recognition, naïve CD4 T-cells undergo clonal expansion and differentiate into effector Th1/Th2 cells. After antigen clearance, the majority of these expanded effector Th1/Th2 cells undergo apoptotic cell death at the contraction phase.6 Some of the effector cells survive for a long time in vivo as memory type Th1/Th2 cells. In developing memory Th cells, several processes, such as (1) cell survival/escape from cell death, (2) proliferation/homeostatic proliferation and (3) the maintenance of Th1/Th2 cell function are required for the successful generation of functional memory Th1/Th2 cells (Fig. 1).

Figure 1. Cellular processes required for the generation of functional memory Th1/Th2 cells.

Figure 1

Cellular processes required for the generation of functional memory Th1/Th2 cells. The details are described in the text. Reproduced from: Nakayama T, Yamashita M. Curr Opin Immunol 2008; 20(3):265-271; with permission from Elsevier.

This chapter summarizes the recent findings on the role of an interesting zinc finger repressor, Schnurri-2 (Shn-2) in the generation and maintenance of memory Th1/Th2 cells. Shn-2 appears to downregulate the NF-κB target genes to maintain a quiescent state and support cell survival of developing memory Th cells at the contraction phase to facilitate the successful generation of memory Th1/Th2 cells.

Schnurri Family Genes

Schnurri (Shn) is a large zinc finger-containing protein; the molecular mass of Shn is -270 kDa (Fig. 2). Shn was originally reported to be a nuclear target in the Drosophila decapentaplegic (Dpp) signaling pathway and interacting with Mad-Medea.7-9 In vertebrates, the Drosophila Dpp signaling pathway may equate to the bone morphogenetic protein/TGF-β/activin signaling pathways that play various roles in developmental processes.10 Vertebrates have at least three orthologues of Shn: Shn-1 (also known as HIV-EP1, MBP-1, PRDII-BF1 and αA-CRYBP1), Shn-2 (also known as HIV-EP2, MBP-2, AGIE-BP1 and MIBP1) and Shn-3 (also known as HIV-EP3, KRC and ZAS3). Although the analysis of Shn-1 in the immune system has not been reported, those for Shn-2 and Shn-3 substantially investigated.

Figure 2. Schematic feature of Schnurri.

Figure 2

Schematic feature of Schnurri.

Shn-3

Shn-3 is the most precisely analyzed molecule among the Shn proteins. It was originally identified as a DNA-binding protein of the heptameric recombination signal sequence required for VDJ recombination of immunoglobulin genes.11 Shn-3 can bind to the NF-κB motif directly and inhibit NF-κB activation.12 Shn-3 interacts with an adopter protein TRAF2 and controls TNF receptor-driven responses.13 Oukka et al demonstrate that the overexpression of Shn-3 inhibited while dominant-negative Shn-3 enhanced NF-κB-dependent transactivation and JNK phosphorylation after TNFα stimulation and regulates the apoptotic cell death and the expression of cytokine genes. Shn-3 also interacts with c-Jun to augment AP-1-dependent IL-2 gene transcription in T-cells. The overexpression of Shn-3 in transformed and primary T-cells leads to increased IL-2 production, whereas Shn-3 deficient T-cells produce decreased IL-2.14 Moreover, the expression of Shn-3 in the regulation of the adult bone mass has previously been reported.15 Shn-3 deficient mice have markedly increased bone mass by promoting Runx2 degradation through the recruitment of E3 ubiquitin ligase WWP1 to Runx2. The survival of Shn-3-deficient CD4+CD8+ double positive thymocytes was reported to be decreased,16 while there was no effect for positive selection in the thymus.14

Shn-2

The mRNA expression of Shn-2 was detected mostly in the brain, heart and immune cells.17-19 Shn-2-deficient mice revealed several important physiological roles of Shn-2 in the immune system. First, Shn-2 is required for positive selection but not negative selection of T-cells in the thymus.20 This defect in positive selection is caused by Shn-2 deficiency in thymocytes but not caused by the deficiency in the thymic stroma cells. In mature T-cells, Shn-2 regulates Th2 cell differentiation by controling GATA3 expression through the regulation of NF-κB activation.21 Shn-2 also regulates memory Th cell generation (described below in detail). Shn-2 is also required for bone development is also reported.22 Interestingly, however, Shn-2 deficient mice have the opposite phenotype in comparison to that of Shn-3 deficient mice. Shn-2 deficient mice have reduced bone remodeling and osteopenia by suppressing NFATc1 and c-fos expression. Shn-2 is involved in the BMP signaling in mammals. Shn-2 interacts with Smad1/4 and C/EBPα upon BMP-2 stimulation and induces the expression of PPARγ2, a key transcription factor for adipocyte differentiation. Shn-2 deficient mice show a reduced amount of the white adipocyte tissue.23

Together, these results indicate that each Shn family gene shares some roles but also the work in different ways and are involved in many different physiological processes.

Role of Shn-2 in Naïve CD4 T and Effector Th2 Cells

Shn-2 deficient mice were mated with OVA-specific TCR Tg (DO11.10 Tg) mice and naïve CD4 T-cells were subjected to in vitro stimulation of Th1/Th2 cell differentiation with OVA peptide and APC.21 As shown in Figure 3A, Th2 cell differentiation was significantly enhanced in Shn-2 deficient T-cell cultures, leaving Th1 cell differentiation unaffected. Based on this observation, the in vivo consequence of the enhanced Th2 cell differentiation was assessed using Th2-driven allergic inflammation models. Shn-2 deficient mice showed enhanced Th2-dependent airway inflammation and airway hyperresponsiveness.24

Figure 3. Enhanced Th2 cell differentiation accompanied with increased NF-κB activity and GATA3 expression in Shn-2-deficient CD4 T-cells.

Figure 3

Enhanced Th2 cell differentiation accompanied with increased NF-κB activity and GATA3 expression in Shn-2-deficient CD4 T-cells. A) Naïve (CD44low) CD4 T-cells from Shn-2-deficient (Shn-2−/−)x DO11.10 Tg mice were purified (more...)

The expression of GATA3, a master transcription factor for the differentiation of Th2 cells is induced in developing Th2 cells through TCR and IL-4 signaling.25,26 In Shn-2 deficient T-cells, the expression of GATA3 at the early time point (e.g., 16 hours after stimulation) after TCR and IL-4 stimulation is up-regulated (Fig. 3B). The induction of GATA3 expression is induced through the activation of the IL-4/Stat6 mediated signal.27 Stat6 deficient T-cells fail to up-regulate GATA3 expression and subsequently Th2 cell differentiation. However, no defects in Stat6 activation after IL-4 stimulation were detected in Shn-2 deficient T-cells (data not shown). In addition, no obvious defect in intracellular Ca2+ influx or Erk1/Erk2 phosphorylation were detected upon TCR stimulation (data not shown), which are reported to be important for the efficient generation of Th2 cells.28,29

Another candidate molecule, which is involved in GATA3 expression, is NF-κB. An important role of NF-κB activation in GATA3 expression was originally reported in the allergic asthma model.30 NF-κB p50 deficient T-cells do not up-regulate GATA3 in in vivo OVA-induced airway inflammation model. In addition, protein kinase C (PKC) θ regulates NF-κB activation and GATA3 expression. In PKCθ-deficient CD4 T-cells, the expression of GATA3 is severely impaired and Th2 cytokine production decreases.31 Therefore, the expression of GATA3 appears to be controlled by NF-κB activation in peripheral CD4 T-cells. As shown in Figure 3C, enhanced activation of NF-κB in both resting and activated T-cells (resting cells: lane 1 vs lane 8, activated cells: lane 2 vs lane 9) is observed in Shn-2 deficient T-cells. In addition, the protein expression of NF-κB (p50 and p65) in both cytoplasmic and nuclear fractions is equivalent between wild-type and Shn-2 deficient cells. Shn-2 directly binds to the NF-κB motif and inhibits the activation of NF-κB. Therefore, the enhanced NF-κB activation in Shn-2 deficient cells appear to be due to the increased binding of NF-κB but not due the increased protein expression of NF-κB (p50 and p65).21

The molecular events operating in naïve CD4 T-cells (quiescent cells) and effector Th2 cells (activated cells) can be illustrated based on these experimental results (Fig. 4, upper two panels). In naïve CD4 T-cells, the expression of Shn-2 is very high (see Fig. 5) and Shn-2 constitutively binds to the NF-κB motif resulting in the expression of the suppressed NF-κB-dependent genes. Through this, naïve CD4 T-cells are able to remain quiescent. However, once CD4 T-cells receive antigenic stimulation through TCR, Shn-2 expression is decreased (see Fig. 5) and NF-κB signaling is activated and increased binding of p65/p50/cofactor is induced. As a result, the transactivation of the NF-κB target genes including GATA3 (Fig. 4, upper right) is induced in developing effector Th2 cells.

Figure 4. Shn-2 and NF-κB activation in naïve, effector and developing memory Th1/Th2 cells.

Figure 4

Shn-2 and NF-κB activation in naïve, effector and developing memory Th1/Th2 cells. The details are described in the text.

Figure 5. Shn-2 expression in the process of the generation of memory Th1/Th2 cells.

Figure 5

Shn-2 expression in the process of the generation of memory Th1/Th2 cells. A) Schematic representation of Shn-2 expression and clone size during the immune responses. B) mRNA expression of Shn-2 in fresh CD4 T-cells from DO11.10 Tg mice, in vitro generated (more...)

Role of Shn-2 in The Generation of Memory Th1/Th2 Cells

The unique expression of Shn-2 in naïve, effector and memory Th2 cells is schematically illustrated in Figure 5A. The expression levels of Shn-2 are high in nave CD4 T-cells and decreased after TCR stimulation and increased again in memory Th1/Th2 cells, particularly in memory Th2 cells (Fig. 5B). The expression of Shn-2 increased quickly even 3 days after cell transfer (Fig. 5C).21

In order to address whether Shn-2 plays a crucial role in the generation of memory Th cells, an in vivo memory T-cell generation assay was performed using adoptive transfer of effector Th1/Th2 cells into syngeneic mice.32 Interestingly, the numbers of Shn-2 deficient Th2 cells significantly decreased in the spleen, lymph nodes and PBMC 7 days after cell transfer (Fig. 6A).21 No difference was detected in the liver and lung at this time point (data not shown). It is possible that Shn-2 deficient Th2 cells proliferate less effectively in vivo. To test this possibility, BrdU was administered three days after cell transfer and the incorporation of BrdU was analyzed. There is no decrease but rather slightly increased BrdU incorporation in Shn-2-deficient cells (data not shown). Consequently, the susceptibility to cell death of Shn-2 deficient T-cells was examined and apparently increased Annexin V+ cells in the spleen, lymph nodes and PBMC were observed (Fig. 6B). In addition, there was a high CD69 and FasL expression on Shn-2 deficient Th2 cells 7 days after cell transfer (data not shown). Similar results were observed in an in vitro culture system. After overnight culture of effector Th2 cells in medium alone, anti-TCR stimulation, or in the presence of IL-7 for 3 days, significantly increased Annexin V+ cells were detected in Shn-2 deficient Th2 cells. Again, increased levels of CD69, FasL and a slightly increase in Bim expression were detected in Shn-2-deficient Th2 cells. However no decrease was detected in Bcl-x, Bcl2 or Mcl1. The same effect was observed in Th1 cells. These results indicate that Shn-2 deficient T-cells show a sustained activated phenotype and are more susceptible to die in vivo and in vitro.

Figure 6. Decreased generation of Shn-2-deficient Th2 cells in the second lymphoid tissues.

Figure 6

Decreased generation of Shn-2-deficient Th2 cells in the second lymphoid tissues. In vitro differentiated effector Th2 cells from DO11.10 Tg Shn-2-deficient mice were transferred into BALB/c nu/nu mice and the mice were analyzed 7 days after cell transfer. (more...)

NF-κB Overexpression in Effector Th Cells Results in the Decreased Generation of Memory Th Cells

Shn-2-deficient T-cells show enhanced NF-κB activation (Fig. 3C) and decreased memory cell generation because of the increased apoptotic cell death (Fig. 6). Therefore, the decreased memory cell generation could be due to the enhanced NF-κB activation in Shn-2-deficient T-cells. Th2 cells overexpressing p65 showed up-regulation of CD69 and FasL even in resting culture with medium. Transfer of the p65 overexpressing Th2 cells resulted in a selective decrease in the cell number in lymph nodes. Thus, Shn-2-mediated repression of NF-κB activation appears to be required for the generation of memory Th cells, particularly those in lymph nodes.

The molecular events operating in the Th cells at the contraction phase are illustrated in Figure 4, lower panel. After antigen clearance, and NF-κB activation decreased the expression of Shn-2 increased. As a result, the transactivation of the NF-κB target genes such as Fas and FasL is decreased and supports Th cell survival to generate memory Th2 cells successfully.

Even at the memory phase (e.g., one or two months after cell transfer), the Shn-2-mediated repression of the NF-κB activation in Th2 cells appears to be required for the maintenance of the proper number of memory Th1/Th2 cells (unpublished observation).

Interesting Questions Raised by the Study on Shn-2

Several interesting observations were noted during the analysis of Shn-2 in memory Th generation. First, the most prominent effect (decreased memory Th cell generation) of Shn-2 deficiency was detected in the lymph node. Shn-2 deficient T-cells express decreased levels of CD62L. CD62L is known to be a homing receptor for the lymph nodes and the expression of CD62L is negatively controlled by the activation of NF-κB. Therefore, it was possible that the decreased Shn-2 deficient memory Th cells in the lymph nodes is due to the decreased homing of Th cells due to the low expression of CD62L. However, this appears not to be the case because the forced expression of CD62L in Shn-2-deficient effector Th cells did not rescue the number of Shn-2-deficient donor cells in the lymph nodes. Another possibility is that T-cell interaction with antigen-loading antigen presenting cells occurs most efficiently in the lymph node resulting in the increased activation induced cell death (AICD).

Second, the defect in the generation of memory cells was more prominent on CD62Lhigh central memory phenotype cells in comparison to CD62Llow effector memory like cells.21 It is likely that the maintenance of CD62Lhigh central memory phenotype cells is more dependent on Shn-2-mediated repression of NF-κB and resulting induction of the quiescence state. However, there is a more interesting possibility at this time. A nonlinear model has been proposed for the differentiation fate of central and effector memory cells33 (see the chapter by Zanetti et al). In this model, it is proposed that the levels of a certain transcription factor determine the differentiation fate of central or effector memory T-cells. Therefore, it is likely that Shn-2 is the first example of a transcription factor, which determines the differentiation fate of central or effector memory T-cells. Shn-2 may direct the differentiation of central memory Th cells.

Conclusion

A series of studies on Shn-2 shed light on several interesting aspects in the development of the memory Th cell system. First, Shn-2 is the first example of a transcription factor that controls cell survival to support the generation of memory Th cells. Second, transcription factors that are induced in activated T-cells are required to be suppressed for the proper formation of memory Th cells. Shn-2-mediated downregulation of NF-κB target genes would be a good example of this possibility. Third, the maintenance of the quiescent state in T-cells (in resting memory Th cells as well as in naïve CD4 T-cells) is an active process mediated by repressor molecules such as Shn-2.

Acknowledgments

This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (Japan) (Grants-in-Aid: for Scientific Research on Priority Areas #17016010; Scientific Research (B) #17390139, Scientific Research (C) #18590466, #19590491 and #19591609, Exploratory Research #19659121 and Young Scientists (Start-up) #18890046: Special Coordination Funds for Promoting Science and Technology and: Cancer Translational Research Project), the Ministry of Health, Labor and Welfare (Japan).

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