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The neonatal immune system: modulation by regulatory T-cells and CTLA-4 (CD152)1)

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Published/Copyright: December 11, 2013
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Laboratoriumsmedizin
From the journal Laboratoriumsmedizin Volume 37 Issue 3

Abstract

The dysregulation of CTLA-4 (CD152), a glycoprotein expressed on the surface of lymphocytes, may lead to chronic inflammation. Based on the recent scientific findings, it has become clear that CTLA-4 inhibits the effector function and, thus, shuts down the effector phase of T-lymphocytes. Interestingly, the CTLA-4-expressing cells become resistant to apoptosis (programmed cell death) and increasingly migrate to the lymph nodes and tissues. Studies have shown that regulatory T cells (Tregs), which switch off unwanted immune responses can inhibit in vivo only if they express an intact CTLA-4 gene. Moreover, it was confirmed that CTLA-4 is not only expressed on T-lymphocytes but also on B-lymphocytes. The mice with genetic inactivation of CTLA-4 show in B-lymphocytes an increased production of IgM antibodies after immunization. Interestingly, in particular, B- and T-lymphocytes from newborns and infants show a strongly increased CTLA-4 expression, suggesting a key immunoregulatory role in neonatal immune responses. Molecules such as CTLA-4, which regulate the differentiation of lymphocytes, could provide therapeutic targets during the early childhood to set the course for protection against autoimmunity and allergy.

Reviewed Publication:

Sack U. Conrad K.

Keywords: antibody; effector T-cell; immune system; infants; lymphocytes; newborns; regulatory T-cell

Introduction

Chronic adaptive immune responses contribute significantly to the pathology of autoimmune diseases, such as juvenile arthritis, juvenile diabetes, and atopic dermatitis. Most adaptive immune responses are regulated in complex ways, and next to the T-cells, B-lymphocytes are essential in the maintenance of immune responses. The primary regulators of T-cells that control their effector function and differentiation are, together with the T-cell receptor (TCR), the homologous co-receptors CD28 and CTLA-4 (CD152) [1–4]. CD28 and CTLA-4 bind the same ligands, CD80 and CD86, on antigen-presenting cells (APC), but CTLA-4 does that with a substantially increased affinity. CTLA-4 signals in T-cells usually have an inhibitory effect [3–5] and regulate already-activated T-lymphocytes during different stages of the T-cell response [1]. Interestingly, polymorphisms in the CTLA-4 gene correlate with the severity of autoimmune diseases (summarized in [1]). Thus, the biological CTLA-4Ig (abatacept) for the therapeutic manipulation of the CD28/CTLA-4 axis of T-cell stimulation proves to be promising in the treatment of chronic inflammation [6] – even though the underlying molecular and cellular mechanisms are only partially understood at this time [7].

CTLA-4-mediated intracellular communication

CTLA-4 as a homodimer binds CD80 dimers, so that a grid-like network is formed (Figure 1) [12–14]. The expression of CTLA-4 on T-cells reaches its maximum 2 days after stimulation when the main functions of CTLA-4 take place [1, 4, 15]. CTLA-4 is transported to the cell membrane by intracellular vesicles, where it is expressed at the immunological synapse in a polarized manner [12, 16]. This tightly controlled localization at the cell membrane represents a major checkpoint to control its inhibitory function [4, 12, 17].

Figure 1 Signal transduction of CTLA-4 in T-lymphocytes (modified according to [1]).CTLA-4 is upregulated not until 1–2 days after T-cell activation [4], and then suppresses the gene expression in general to terminate the T-cell response. (A) In unstimulated T-lymphocytes, CTLA-4 binds AP-50 and PP2A, thereby facilitating its internalization [8]. (B) New findings show that the role of CTLA-4, especially on activated T-lymphocytes, is complex. After the stimulation of T-lymphocytes, CTLA-4 binds intracellular PI3 kinase and, probably indirectly, Shp-2 [9]. Here, the CTLA-4 signals can switch off gene expression, but also activate enzymes. Already activated T-lymphocytes are inhibited in their proliferation by CTLA-4 [4]. CTLA-4 signals also induce PI3 kinase-dependent survival in already activated T-lymphocytes, and CTLA-4 signals facilitate migration along the chemokine gradient [10, 11]. Surviving lymphocytes at the end of an immune response could be precursors of memory cells. In B-lymphocytes, the proximal signal transduction of CTLA-4 is completely unknown.
Figure 1

Signal transduction of CTLA-4 in T-lymphocytes (modified according to [1]).

CTLA-4 is upregulated not until 1–2 days after T-cell activation [4], and then suppresses the gene expression in general to terminate the T-cell response. (A) In unstimulated T-lymphocytes, CTLA-4 binds AP-50 and PP2A, thereby facilitating its internalization [8]. (B) New findings show that the role of CTLA-4, especially on activated T-lymphocytes, is complex. After the stimulation of T-lymphocytes, CTLA-4 binds intracellular PI3 kinase and, probably indirectly, Shp-2 [9]. Here, the CTLA-4 signals can switch off gene expression, but also activate enzymes. Already activated T-lymphocytes are inhibited in their proliferation by CTLA-4 [4]. CTLA-4 signals also induce PI3 kinase-dependent survival in already activated T-lymphocytes, and CTLA-4 signals facilitate migration along the chemokine gradient [10, 11]. Surviving lymphocytes at the end of an immune response could be precursors of memory cells. In B-lymphocytes, the proximal signal transduction of CTLA-4 is completely unknown.

Studies on T-helper (Th) cells showed that CTLA-4 inhibits T-cell responses, whereas other co-stimulatory molecules, such as the CTLA-4 homologue CD28, activate T-cell responses. Consequently, the homologues CD28 and CTLA-4 facilitate various properties of the T-cell: Signals via CD28 facilitate IL-2 production and T-cell proliferation – processes that are counter-regulated by CTLA-4 by inhibiting IL-2 transcription and the cell cycle [1, 13, 14, 18, 19]. CD28 signals lead to increased stabilization of the IL-2 mRNA and upregulate Bcl-xL – functions that are not counter-regulated by CTLA-4 [13, 18]. CD28 binds PI3 kinase (PI3K), the Grb-2 adaptors and the phosphatase PP2A, while CTLA-4 binds PI3K and the phosphatases PP2A and Shp-2 (summarized in [4, 13, 20]). The linking of CD28 and CTLA-4 to various signal mediators shows that CTLA-4 neither simply regulates CD28 signaling, nor merely blocks the TCR signal [1, 4, 13, 18].

The main function of CD8 T-cells is the cytotoxic lysis of degenerated and infected cells. Upon activation, CD8 T-cells express CTLA-4 on their surface more frequently than CD4 T-cells [20]. Upon first contact with the antigen, neither their proliferation nor apoptosis is controlled by CTLA-4, but certainly their IFNγ production is. We were able to show that this is achieved by selective regulation of the transcription factor eomesodermin [21]. Eomesodermin regulates in CD8 T-cells both IFNγ and effector molecules of the cytotoxic lysis. The expression of T-bet, the central transcription factor for the IFNγ gene, remains unchanged in this process. Since CTLA-4 inhibits in particular the IFNγhigh producers, it is suggested that CTLA-4 therefore also affects the pool of memory cells [22].

CTLA-4 in the differentiation of T-lymphocytes

The observation that surface-expressed CTLA-4 is detectable exclusively on already activated lymphocytes implies that it plays a central role here [4]. We have shown that CTLA-4 facilitates critical functions of already activated T-lymphocytes: Suppression of T-cell proliferation [4], suppression of effector functions [20, 21], induction of survival [10] and migration of T-lymphocytes [23]. Lymphocytes that receive a CTLA-4 signal are stopped in their proliferation and survive [1]. Lymphocytes that do not express CTLA-4 will briefly proliferate more strongly to eliminate foreign pathogens, but then they die [10]. This ensures that the immune response is stopped. In addition, T-lymphocytes that receive a CTLA-4 signal migrate along inflammatory and homeostatic chemokine gradients [23, 11]. The lymphocytes surviving at the end of an immune response and migrating to memory areas might be potential precursors of memory cells. Memory cells contribute significantly to the course of chronic disease in autoimmune processes. Our recent findings on biochemical and functional consequences of CTLA-4-mediated effects of already activated lymphocytes are summarized together with the known signal transduction of CTLA-4 in Figure 1. Among other things, the model shows the independent functions of CTLA-4, newly described by us, during the late T-cell differentiation (Figure 1, gray boxes).

CTLA-4 induces specific migration of Th1 lymphocytes

Almost all antigen-experienced cells infiltrating non-lymphoid tissue express the chemokine receptor CCR5. Previously it was shown that CTLA-4 facilitates the surface expression of CCR5 on Th1 lymphocytes. But the membrane expression of CCR5 [24] does not allow for conclusions about migration, because chemokine receptors pass their signals on through G-proteins, which are often present in the inactive state. We set up in vitro migration experiments to analyze the specific migration of Th1 lymphocytes in vitro [23, 11]. Here, the endothelium is replaced by a membrane. We have shown for the first time that Th1 lymphocytes whose CTLA-4 gene was inactivated migrate much less along the inflammation-associated chemokine Mip1β (CCL4) than Th1 lymphocytes with an intact CTLA-4 gene. We confirmed the results by triggering or not a CTLA-4 signal to pre-activated Th1 lymphocytes. Th1 lymphocytes that have received a CTLA-4 signal migrate significantly better and more specifically along a Mip1β gradient than lymphocytes that have not received a CTLA-4 signal.

The molecular mechanisms of the differentiation of T-lymphocytes initiated by CTLA-4 have not been clarified. We have shown so far that in the CTLA-4-mediated modulation of T-cell functions, such as proliferation and cytokine production [3, 4, 18, 20], but also in connection with activation-induced cell death (a form of apoptosis), CTLA-4 signals interfere differentially with gene expression by inhibiting the activation of key transcription factors such as NFAT, eomesodermin, GATA3, and FKHRL1 (but not cKrox, AP1, or T-bet!). In particular, we have been able to show that CTLA-4 induces the expression of Bcl-2 and of the chemokine receptor CCR5, and activates the enzyme activity of PI3 kinase [10, 11, 24].

CTLA-4 in the B-cell differentiation

B-cell functions go far beyond the production of antibodies, ranging from antigen presentation for T-lymphocytes and co-stimulatory function by expression and production of surface molecules to the production of cytokines, which influence the differentiation of B and T-lymphocytes. Similar to the activation and effector functions of the T-lymphocytes, the functions of B-lymphocytes are also controlled by co-stimulation. Molecules, such as CD40 and CD30, can pass on co-stimulatory signals to B-lymphocytes when they are stimulated by their ligands on T-lymphocytes [19]. Our data imply that CTLA-4, in addition to the effect on these molecules, controls the differentiation and effector function of B-lymphocytes after they have been activated [20, 25].

For the first time, we were able to clearly underscore indications [26, 27] that proposed B-lymphocytes to express CTLA-4: We could show that mRNA of CTLA-4, intracellular CTLA-4, and membrane-bound CTLA-4 are also expressed by activated B-lymphocytes [25]. The surface expression reaches its maximum 48–72 h after activation of B-lymphocytes in B-/T-cell co-cultures. To understand the function of CTLA-4 on B-lymphocytes, we generated chimeric animals with the combined transplantation of bone marrow from B-cell-deficient animals and bone marrow from CTLA-4-/- animals at a ratio of 80% to 20% and thereby created mice in which CTLA-4 is deleted only in all B-lymphocytes [25]. A thymus-dependent in vivo immunization of these chimeras resulted in an increased IgM production after primary and secondary immunization [25].

The neonatal immune system primarily has B1-lymphocytes in the B-cell compartment. These B1-lymphocytes exhibit characteristics of regulatory cells, i.e., they are able to inhibit T-cell responses. Toll-like-receptor (TLR) stimulation of murine neonatal B-lymphocytes had shown that they caused anti-inflammatory effects [28]. They facilitate the suppression of T-lymphocytes through secretion of IL-10. Our preliminary work show that these neonatal B-lymphocytes express CTLA-4 (data not shown). It seems reasonable to assume that also regulatory B-lymphocytes can use CTLA-4, as it was shown for regulatory T-lymphocytes (Treg) (see below).

CTLA-4 and Treg cells

Treg cells play an important role in the suppression of unwanted immune responses. Natural occurring Treg (nTreg) cells (CD4+CD25+FoxP3+) are formed in the thymus. The nTreg cells have the ability to inhibit in vivo autoimmune diseases as well as to suppress antigen-specific T-cell proliferation in vitro and T-cell proliferation in response to allogeneic cells [29, 30]. Decreased numbers of Treg cells or even Treg cell functions were detected in patients with autoimmune diseases, such as type 1 diabetes, lupus erythematosus, rheumatoid arthritis or multiple sclerosis [31].

Treg cells suppress the activation and expansion of inflammatory T-cells. CTLA-4, which is expressed by these cells constitutively, is fundamental for this function of Treg cells. Thus, Treg cells from CTLA-4-/- mice are formed at a higher rate, but cannot perform their regulatory function [32]. The immunosuppressive effect of Treg cells can be mediated by means of soluble pleiotropically acting factors such as TGF-β and IL-10 [29, 33]. In addition, modes of action through direct cell contact have also been described [29]. The binding of the CTLA-4 molecule on Treg cells to its ligands CD80 and CD86 (B7) induces the reduction of the B7 expression on dendritic cells, for example, by direct trans-endocytosis, so that fewer CD28 signals are possible [34]. Thus, Treg cells actively engage in the process of T-cell differentiation and may also influence the formation of memory cells. First indications show that nTreg cells promote the formation of multi-functional memory cells via CTLA-4 [35].

It has been clearly shown that CTLA-4 expression is essential for the Treg cells, so that they can have a regulatory effect in vivo [32, 36]. We have shown that CTLA-4-/- mice that die at the age of 3–5 weeks generate a lot of Treg cells, but these are not competent. But Treg cells without CTLA-4 do not aquire a pro-inflammatory phenotype [37]. Injections of CTLA-4-expressing Treg cells in neonatal CTLA-4-/- mice prolonged their lives dramatically [32].

CTLA-4 expression on CD4 T-lymphocytes of neonates

The neonate is faced with a major challenge at birth: Its immune system must now also cope with a wealth of new antigens from the environment and differentiate them from the “self.” In addition, its immune system must recognize when it is sensible to react against foreign antigens, as in the case of bacteria. So that the organism of the neonate is not damaged by excessive own immune responses, or actually generates memory cells that harm the organism perspectively, it reacts hypo-reactively (summarized in [38]). To ensure this protection, regulatory mechanisms of the immune system are actively at work. Our recent studies show that in the early childhood immune system, the expression of CTLA-4 on CD4 T-lymphocytes is regulated in an age-dependent manner (Figure 2). Using a real-time PCR, we could show that in the context of an alternative T-cell stimulation via anti-CD3 and anti-CD28, CD4 T-lymphocytes of neonates exhibit a significantly higher increase in the CTLA-4 expression compared to adults. This illustrates that the neonatal immune system uses the CTLA-4 molecule in the regulation of its lymphocytes. In fact, it is known from fetuses that they already form Treg cells that are increasingly carrying CTLA-4 on their surface [38, 40]. In the fetus, up to 12% of the CD4 T-lymphocytes occur as Treg cells; in adults, their percentage is only 5%. The earlier a child is born, the higher is the proportion of Treg cells. The difference is explained by the ontogenetically different development of Treg cells [41]. In the fetus, the hematopoietic stem cells produce mainly Treg cells; in adults, T-lymphocytes with effector potential. Probably both developmental scenarios occur in neonates in parallel – the precise point in time when this is converted to adult is not yet known.

Figure 2 Neonatal T-lymphocytes increasingly express CTLA-4.Quantitative real-time PCR to study the regulation of CTLA-4 mRNA expression in the naive CD4 T-lymphocytes of neonates and adults. The naive CD4 T-lymphocytes were activated on day 0 with anti-CD3 and anti-CD28-coupled microbeads [39]. This shows in each case the time-dependent CTLA-4 mRNA expression in CD4 T-lymphocytes of three neonates (black symbols) and two adults (white symbols). A and B differentiate stimulated T-lymphocytes of a donor from rich (A) or less rich (B) culture media. Without a letter code, the stimulations were carried out in a rich culture medium, same as for A.
Figure 2

Neonatal T-lymphocytes increasingly express CTLA-4.

Quantitative real-time PCR to study the regulation of CTLA-4 mRNA expression in the naive CD4 T-lymphocytes of neonates and adults. The naive CD4 T-lymphocytes were activated on day 0 with anti-CD3 and anti-CD28-coupled microbeads [39]. This shows in each case the time-dependent CTLA-4 mRNA expression in CD4 T-lymphocytes of three neonates (black symbols) and two adults (white symbols). A and B differentiate stimulated T-lymphocytes of a donor from rich (A) or less rich (B) culture media. Without a letter code, the stimulations were carried out in a rich culture medium, same as for A.

Conclusions

The co-stimulatory molecule CTLA-4 with its inhibitory effect is expressed not only on T-lymphocytes but also on B-lymphocytes, and is relevant to CD4, CD8, and humoral B-cell responses in vivo. The previously described effects of CTLA-4 signals on activated Th-lymphocytes, such as deactivation, protection from activation-induced cell death, recruitment to the pool of memory cells, regulation of migration – along with the increased expression of CTLA-4 on neonatal lymphocytes – suggest a central role in the restrictive limitation of immune responses during infancy and thus in preventing chronic immune pathologies. This central immunoregulatory role of CTLA-4 in neonatal immune responses provides a new target for therapeutic strategies in order to pave the way for an immune system that already protects in childhood from autoimmunity and allergies.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Research funding: This study was funded by the German Research Foundation (Br 1860/6).

Employment or leadership: None declared.

Honorarium: None declared.

Corresponding author: Prof. Dr. Monika C. Brunner-Weinzierl, Experimentelle Pädiatrie und Neonatalogie (Experimental Pediatrics and Neonatology), Universitätskinderklinik (University Children’s Hospital), Universitätsklinikum Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany, Tel.: 0391/6724003, Fax: 0391/6724202, E-Mail:
  1. 1)

    Original German online version at: http://www.degruyter.com/view/j/labm.2013.37.issue-3/labmed-2012-0061/labmed-2012-0061.xml?format=INT. The German article was translated by Compuscript Ltd. and authorized by the authors.

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Received: 2013-11-18
Accepted: 2013-11-18
Published Online: 2013-12-11

©2013 by Walter de Gruyter Berlin Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  10. Comparison of ordinary linear regression, orthogonal regression, standardized principal component analysis, Deming and Passing-Bablok approach for method validation in laboratory medicine
  11. Buchbesprechung/Book Review
  12. Lexikon der Medizinischen Laboratoriumsdiagnostik
https://doi.org/10.1515/labmed-2013-0067
Keywords for this article
antibody; effector T-cell; immune system; infants; lymphocytes; newborns; regulatory T-cell
Creative Commons
BY-NC-ND 3.0

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  5. The neonatal immune system: modulation by regulatory T-cells and CTLA-4 (CD152)1)
  6. Originalarbeiten/Original Papers
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  10. Comparison of ordinary linear regression, orthogonal regression, standardized principal component analysis, Deming and Passing-Bablok approach for method validation in laboratory medicine
  11. Buchbesprechung/Book Review
  12. Lexikon der Medizinischen Laboratoriumsdiagnostik
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