Sarah Boudaly

Unite Mixte de Recherche 7151 Centre National de la Recherche Scientifique, Universite Denis Diderot Paris 7, Institut Universitaire d'Hematologie, Hopital Saint-Louis, Paris, France

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. Discussion

3.1. Accession of DCs to the antigen presenting cell status

3.2. Neutrophils as regulator cells of the adaptive immune response

3.3. Neutrophils attract DCs

3.4. Activated neutrophils deliver both activation signals and antigen to DCs

3.5. Molecular mechanisms of neutrophil-DC communication

3.6. Do dying neutrophils regulate DC activation?

3.7. Conclusion 4. Acknowledgement

5. References

1. ABSTRACT

The obsolete view describing neutrophils as innate immune cells that respond rapidly to microbial invasion and then rapidly die by apoptosis is now challenged by several data. In both human and mice, there are now evidences that neutrophils play a role in dendritic cell activation, a critical step for the outcome of the specific T cell response.

2. INTRODUCTION

Neutrophils and DCs, that are located in distinct anatomical compartments during the steady state (the blood for neutrophils and the peripheral as well as the lymphoid organs or tissues for DCs), meet at inflammatory sites during an immune response (figure 1). Strikingly, despite this obvious observation, the question of neutrophil-DC interactions and the consequences of this cross-talk have been ignored for long time. This situation probably relates to the old view that neutrophils are inflammatory but not immune cells, whereas DCs act as professional antigen presenting cells able to initiate very efficiently T cell specific responses in the lymphoid organs. In addition, most scientists have been probably discouraged from studying neutrophil functions because these leukocytes are short lived cells that rapidly undergo spontaneous apoptosis (1-3).

However, an increasing number of recent data started to enlighten this new field of cellular interactions between neutrophils and the leukocytes that are involved in "specific immunity", leading to the breakdown of a dogma. In this article, I will focus on the interactions that take place between neutrophils and DCs and the impact of this cross-talk on DC activation.

3. DISCUSSION

3.1. Accession of DCs to the antigen presenting cell status

DCs are highly efficient in stimulating T lymphocytes and deliver signals that are critical for the further polarization of the adaptive immune response and, in this regard, are defined as professional antigen presenting cell (APC) (4). However, to perform their APC functions, DCs need to be activated.

DCs are located in almost all anatomical sites including mucosal tissues, skin and vascularized organs. In the steady state, peripheral DCs express low surface levels of major histocompatibility complex (MHC) class II and co-stimulatory molecules, and do not secrete immune cytokines. They are not efficient at stimulating T cell responses and, in this regard, they are referred to as immature DCs (iDCs). However, in the early phase of the immune response, iDCs detect microorganisms or foreign structures via receptors that recognize molecular motifs expressed by a large spectrum of microorganisms called pathogen-associated-molecular pattern -PAMPs-. These pattern recognition receptors (PRRs) include Toll-like (5), C-type lectin (6) and Nod receptors (7-9). Other receptors -Fc (10-12) or complement receptors (13)- are then involved in uptake of immune complexes or opsonized microorganisms. iDCs not only detect microorganisms but also sense the tissue environment to detect endogeneous stress signals: apoptotic cells via expression of scavenger receptors CD36, a_vb₅ or a_vb_{3 (}14, 15) or danger-associated molecules released by injured or necrotic cells such DNA, RNA, heat shock proteins or hyaluronic acid (16-18) (figure 2) .

Such sensitized DCs process antigens and undergo a complex and coordinated program of phenotypic, morphological and functional changes referred to as "DC activation/maturation process". This progression includes upregulation of MHC class II, CD80, CD86 and CD40 molecules, the secretion of cytokines and chemokines, the expression of chemokines and cytokines receptors (figure 2) and the loss of phagocytic functions. Such activated DCs take part locally to the innate response by secreting inflammatory cytokines (IL-1a, TNF-a, IL-6) (19) and acquire the capacity to migrate to the draining lymph node, where they will further select and initiate the pool of naïve specific T lymphocytes.

The signals delivered by DCs to T lymphocytes are critical in directing immunity (Th1, Th2, Th17) (20-23) or tolerance (regulatory T cells) (24-28), or anergy (29) induction. The outcome of the immunological response depends on the DC status that is influenced by the stimuli to which DCs have been exposed prior to encounter T lymphocytes in the lymph nodes (17, 30). DC activation is influenced by the nature of the initial signal, i.e, bacteria, viruses, fungi, drugs, apoptotic or necrotic cells. However, DCs are sparse in peripheral tissues and surrounded by other resident professional phagocytes -such as macrophages and mast cells- or rapidly recruited inflammatory cells that might influence their response. In the case of tissue injury, neutrophils, circulating in large numbers in blood, are massively recruited to the injured site and can play a pivotal role in DC activation/maturation processes.

3.2. Neutrophils as regulator cells of the adaptive immune response

In vivo depletion of neutrophils in animal models revealed that these "phagocytic non-specific effectors" of the innate response play a significant role in induction of the T cell specific activation (31, 32). Neutrophils indeed interfere with the T cell response through the production of T cell recruiting chemokines (32, 33). They also have the potential to acquire APC functions to instruct directly CD4 (34) (32, 35-37) or CD8 lymphocytes (31), during a process called "transdifferentiation". Moreover, neutrophils can perform cross-presentation of antigens to CD8 T cells (38, 39) (figure 3).

However, evidences obtained in both human and mouse systems, indicate that neutrophils influence adaptive immunity not only by T cell recruitment and activation but also by instructing DCs that are instrumental in directing T cell responses against exogenous as well as endogenous antigenic materials.

3.3. Neutrophils attract DCs

In vitro studies revealed that neutrophils attract DCs through the production of chemotactic factors. Human neutrophils activated by various stimuli -TNF-a , IFN-g, bacteria, or bacterial-derived products (LPS, fMLP)-, release a large pattern of chemotactic factors including CCL19 and CCL20 chemokines (33, 40-42) and b-defensins that selectively attract iDCs (43, 44). In the mouse system, Toxoplasma Gondii-stimulated neutrophils secrete CCL3, CCL4, CCL5 and CCL20 chemokines (45). Interestingly, activated DCs in turn produce high amounts of CXCL-8 that mediates both recruitment and activation of neutrophils (46). Thus, in an inflammatory situation, neutrophils and DCs attract each other to favour their encounter (figures 4, 5).

Neutrophils also play a role in the replenishment of iDCs at the inflamed site, since they produce CCL2, CCL3, CCL4 and CCL20 that recruit distinct subtypes of blood DC precursors (47).

3.4. Activated neutrophils deliver both activation signals and antigen to DCs

Two independent in vitro studies using human neutrophils and monocyte-derived DCs showed that both cell types physically associates to form heterologous clusters within 30 minutes (48, 49). In both models, and beyond some discrepancies that probably relates to differences between these experimental systems, live activated neutrophils induce upregulation of MHC class II, CD86, CD40 or CD83 on DC surface and IL-12 production (figure 4) via a cell-contact-dependent pathway. According to these results, DCs that have been exposed for less than 18 hours to neutrophils are more potent in stimulating naïve T cells in an MLR and direct the T cell response to the production of Th1 cytokines rather than Th2 (49). Similar results were obtained in the mouse system, where Toxoplama Gondii- or LPS-stimulated neutrophils have been shown to induce upregulation of MHC class II, CD40, CD80 and CD86 molecules on iDCs as well as IL-12 and TNF-a secretion (45, 50, 51) (figure 5).

In human systems, we showed that live neutrophils deliver Candida albicans (48) to iDCs via a cell-contact dependent mechanism for subsequent T cell presentation. This indicates that antigenic material first captured by neutrophils and further available for uptake and presentation, can be transferred to DCs during the cellular interaction between both cell types (figure 6).

3.5. Molecular mechanisms of neutrophil-DC communication

In human, cell-contact-dependent interactions between neutrophils and DCs are required to observe DC activation (48, 49). However, the molecular mechanisms involved differ between these two models. In the work by van Gisbergen et al. DC-specific ICAM-3-grabbing non integrin (DC-SIGN) expresses on iDCs binds neutrophil-specific glycoforms of Mac-1 (CD11b/CD18) and CEACAM1 (49, 52). The DC-SIGN ligand recognized in the Mac-1 complex is located on the a_M chain (CD11b). In contrast, we showed that direct contact between neutrophils and iDCs and the subsequent DC activation are dependent of CD18 expression on the neutrophils and did not involve DC-SIGN on the DC surface. These discrepancies could however be explained by differences between the experimental approaches. First, activation of neutrophils was not performed with the same stimuli, that were LPS, fMLP or TNF-a in the van Gisbergen studies (49), and GM-CSF and IL-4 in ours (48). The nature of the stimulating signal delivered to the neutrophil may probably direct the molecular pathway further involved in neutrophil-DC communication. Secondly, although we showed that CD18 is critical for neutrophil-DC interaction, we cannot exclude involvement of CD11b in our model (48). Indeed, saturation of CD11b molecules on freshly isolated or GM-CSF-activated neutrophils was never achieved with anti-CD11b blocking antibodies (such as clones ICRF44 or IB4), even at high concentrations (25 mg/ml/10⁶ cells) (data not shown), a situation that prevents inhibition of CD11b-dependent cellular interactions. Identification of CD11b as a ligand of DC-SIGN, was demonstrated using molecular and biochemical approaches (western blot, ELISA and binding experiments using immunoprecipitated neutrophil-derived proteins and recombinant DC-SIGN) instead of neutrophil-DC co-cultures with anti-CD11b inhibiting antibodies (49). Moreover, neutrophil-induced CD83 upregulation was not inhibited on DCs in the presence of anti-CD11b blocking antibodies (52). It appears, however, from both human studies that the CD11b/CD18 complex, that is involved in several neutrophil functions including cell-adhesion, transmigration, phagocytosis of microorganisms and apoptosis (53), is also required for neutrophil-DC crosstalk (figure 7).

In both human (49) and mouse models (45, 51), the local production of TNF-a by neutrophils physically associated or close to DCs is required to induce DC activation.

3. 6. Do dying neutrophils regulate DC activation?

The process of neutrophil activation is closely linked to that of cell survival (2, 54). Indeed, resting neutrophils are short lived cells, with a circulating half-life of less than 24 hrs and it is now well established that this dramatic neutrophil elimination is mediated by the constitutive activation of an apoptotic cell death program. Because the innate-immune response to infection is critical, this "naturally occurring" apoptosis can be delayed within the inflammatory environment, a process that may be advantageous for host defense. However, after they have been recruited and activated, neutrophils undergo apoptosis (or in some cases necrosis) and are cleared from the inflammated tissue by resident phagocytes (3). Uptake of dying cells, apoptotic or necrotic, by iDCs have been reported to promote antigen acquisition by DC for subsequent T cell presentation (14). In agreement with these finding, it has been shown that human apoptotic neutrophils that have phagocyted C. albicans (48)or Mycobacterium tuberculosis (55) can transfer to DCs antigens for further T cell presentation or cross presentation, respectively. Although, apoptotic neutrophils deliver efficiently antigens to iDCs (48, 55, 56), they are not able to induce upregulation of DC activation markers and/or cytokine production. This inhibitory effect could however be overcomed in the presence of proinflammatory factors such TNF-a or microorganism-derived signals.

3.7. Conclusion

The concept that neutrophils contribute directly to the adaptive immune response is now sustained by studies indicating that neutrophils associate with iDCs and deliver to them both activation signal and antigen material, allowing them to progress toward the professional APC status. In human and mouse studies, the neutrophil-DC communication have been studied using iDCs, mimicking the in vivo situation in peripheral injured tissues. However, it will be of great interest to investigate the effect of neutrophil on mature DCs. Indeed, in vivo data showing that antigen-bearing neutrophils can exit the inflammated tissue to migrate into the draining lymph nodes in close contact with DC and T cells have been reported in different models (57-59). In vitro, it has been shown that human neutrophils are able to migrate across the endothelial barrier in a reverse direction (60). The description and the understanding of a triangular relationship between neutrophil-DC and T cells in secondary lymphoid organs will probably emerge soon and will be the next conquest of the neutrophil in the land of immunologists.

4. ACKNOWLEDGMENTS

I wish to thank Marco Cassatella and Nathalie Winter for helpful discussions and critical reading of the manuscript.

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Key Words : Neutrophil, Dendritic Cell, Cellular Cooperation, Innate Immunity, Review