Type I interferon as a stimulus for cross-priming

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Cytokine & Growth Factor Reviews 19 (2008) 33–40 www.elsevier.com/locate/cytogfr

Type I interferon as a stimulus for cross-priming Agne`s Le Bon a,*, David F. Tough b,1 a

b

INSERM U591 – Marie Curie Excellence Team, AVENIR Group, Faculte´ Necker, 156 rue de Vaugirard, 75015 Paris, France T Cell Regulation Group, Target Discovery, riCEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom

Abstract Type I interferon (IFN-a/b) is induced rapidly by infection and is well recognised for its crucial role in innate defence. However, it is evident that IFN-a/b also serves as a signal for the generation of adaptive immune responses. In this review, we focus on the involvement of IFN-a/b in the induction of CD8+ T cell responses by cross-priming. # 2007 Elsevier Ltd. All rights reserved. Keywords: IFN-a/b, Cross-priming; Dendritic cells

1. Introduction CD8+ T cells represent important mediators in defence against many infectious agents. Priming of CD8+ T cell responses requires that these cells initially recognise pathogen-derived antigenic peptides on the surface of specialised antigen-presenting cells (APCs). Since infections can be restricted to non-APCs (for example, certain viruses selectively infect epithelial cells), priming of CD8+ T cell responses is a logistical challenge for the immune system. To cope with invaders that do not infect APCs directly, a strategy called cross-priming, in which APCs acquire antigen for presentation by capturing infected cells, is employed [1,2]. Effective stimulation of T cell responses by cross-priming necessitates that APCs not only internalise exogenous antigens and present these to CD8+ T cells, but also that the APCs receive signals that activate (or license) them to induce a productive immune response. Notably, licensing signals are linked with the infectious process itself; APCs recognise components of pathogens through germline encoded innate receptors and can also detect mediators produced by infected cells. In addition to licensing APCs, * Corresponding author. Tel.: +33 1 40 61 53 62; fax: +33 1 40 61 55 80. E-mail addresses: [email protected] (A. Le Bon), [email protected] (D.F. Tough). 1 Tel.: +44 1438 764 552; fax: +44 1438 764 582. 1359-6101/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2007.10.007

the same signals may act on other immune cells to promote the response. Production of type I interferon (IFN-a/b) is a common response of mammalian cells to infection. Although IFN-a/ b has long been recognised to be a crucial mediator of innate defence, particularly against virus infection, recent research has shown that this cytokine also makes an important contribution to the generation of adaptive immune responses. In this review, we focus on the role that IFNa/b plays in cross-priming.

2. Recognition of antigen by CD8+ T cells CD8+ T cells recognise, through clonally-distributed T cell receptors (TCR), antigenic peptides presented in association with MHC class I molecules. Peptide-MHC class I complexes can be generated from antigens via director cross-presentation pathways. In this context, the term direct presentation denotes that peptides are derived from proteins synthesised within the cell in which they are presented; this can include both cellular proteins and the products of intracellular viruses or bacteria. Conversely, cross-presentation refers to the presentation of peptides from exogenous proteins, i.e. proteins that have been captured (either as protein alone or protein associated with another cell) by the APC. While an in depth description of antigen

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processing and presentation is beyond the scope of this review, the basic processes involved in the two MHC class I presentation pathways are discussed briefly below. 2.1. Direct presentation MHC class I molecules on healthy (non-infected) cells constitutively present peptides that are derived from the proteolytic degradation of polypeptides expressed within the cells. The presented peptides appear to be generated largely from newly synthesised proteins, which allows for the presentation of pathogen-derived peptides very soon after infection. A proportion of newly synthesized proteins, which may be defective ribosomal products [3], are ubiquinated and then degraded into peptides by a large catalytic protease complex called the proteasome [4,5]. The resulting peptides are transported from the cytoplasm into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP) and loaded into new MHC class I molecules in the lumen of the ER. Proper folding and subunit assembly of MHC class I molecules and peptide loading are regulated by various molecular chaperones [6,7]. Once formed, peptide-MHC class I complexes are rapidly transferred through the Golgi apparatus to the cell surface where they can be presented to CD8+ T cells. 2.2. Cross-presentation Evidence that MHC class I-associated peptides can also derive from proteins not expressed within the APC came initially from studies showing that CD8+ T cell responses could be primed following immunisation with cells that expressed the antigen but lacked the restricting MHC class I molecules [8,9]. Two mechanisms have been described by which this cross-presentation can occur. Firstly, antigens internalized by phagocytosis or pinocytosis have been shown to intersect the ER – MHC class I loading pathway after phagosomes or pinosomes contact with ER-like compartments. Similarly to direct presentation, this process is TAPdependent [10–13]. While this is thought to be the main pathway for cross-presentation [5], a second, TAP-independent mechanism has also been reported [14–16]. In this, crosspresentation occurs when peptides from the acquired antigen are loaded into recycling MHC class I molecules in endosomes. The extent to which this pathway contributes to cross-presentation may depend on the antigen-presenting cell type and the route by which the antigen is internalised.

3. Dendritic cells A large body of evidence supports the view that dendritic cells (DCs) are the crucial APCs for the initiation of T cell responses, including the induction of cross-priming. However, it is also clear that DCs are heterogeneous and play multiple roles in the immune system. DC function is

integrally linked with the ability of these cells to alter their properties in response to environmental signals. In general, DCs are considered to convert from an immature state, in which they are poor stimulators of immune responses, to a mature state, in which they exhibit potent T cell stimulatory ability, upon detection of infection or other signs of potential danger to the host. Depending on the specific maturation signals they receive, DCs acquire the capacity to drive different types of immune responses. In addition to such functional plasticity, it is evident that distinct subsets of DCs exist. Accordingly, heterogeneity amongst DCs is associated with variation in their ability to induce cross-priming. 3.1. DC subsets DC heterogeneity has been best characterised in mice, where several DC subsets have been identified. In the spleen, CD11c+ DCs can be subdivided based on their expression of CD8a and CD4 into CD8a CD4 (DN), CD8a CD4+ (CD4+) and CD8a+ CD4 (CD8+) subpopulations [17]. These cells, plus two additional DC subsets derived from the epidermis (Langerhans cells) and dermis (dermal DCs) are found in the skin-draining lymph nodes [18]. The cells in these five DC subsets are generally referred to as conventional DCs, as their primary role in the immune system appears to be in antigen presentation (although the precise function of some subsets remains to be determined). Other DCs have also been described for which an antigen presentation role is much less clear. Principal among these is the plasmacytoid DC (PDC) subset. These cells are renowned by their ability to produce large amounts of IFN-a/b after viral stimulation [19,20]. In addition, a population of DCs, termed interferon-producing killer DCs (IKDCs), has been reported to possess natural killer-like activity and to produce large amounts of IFN-g [21]. 3.2. DCs and cross-presentation While macrophages [22–24], B cells [25,26] and DCs [27,28] have all been shown to cross-present antigens in vitro, DCs appear to be both sufficient and necessary for cross-priming of CD8+ T cells in vivo [29,30]. DCs are constitutively able to cross-present, but DC maturation may enhance this process [31–33]. When directly loaded with peptide, CD8a+ and CD8a splenic DCs do not exhibit obvious differences in their ability to prime naı¨ve CD8 T cells. However, these APCs appear to differ markedly in their ability to cross-prime CD8+ T cells. In support of this notion, CD8a+ DCs have been found to crosspresent antigen much more efficiently than CD8a DCs after in vivo immunisation by the i.v. route [34,35]. Since PDCs appear to be completely unable to stimulate CD8+ T cell responses by cross-priming [36,37], CD8a+ DCs seem to be the main APCs capable of cross-presentation in the spleen. Interestingly, lymph node resident CD8a+ DCs have been shown to stimulate cross-priming of virus specific CD8+ T

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cells following infection of dermal DCs by HSV-1, indicating that this subset of DCs also contributes to cross-priming in the lymph node [38]. Of note, the superior cross-presentation ability of CD8a+ DCs does not appear to be due to a better ability to capture exogenous antigen, and thus may be related to the activity of particular antigen processing and presentation pathways within these cells [39].

4. Cross-priming versus cross-tolerance Cross-presentation of antigen by DCs is necessary but not sufficient for cross-priming. DCs also need to receive appropriate activation signals to become competent to induce cross-priming, a process which has been referred to as ‘‘licensing’’. Cross-presentation of antigen by unlicensed DCs stimulates an abortive CD8+ T cell response that culminates in tolerance rather than induction of effector T cells (cross-tolerance). Various models of cross-presentation have been shown to lead to cross-tolerance and this phenomenon is thought to play an important role in establishing self-tolerance to tissue antigens [40–42]. One mechanism by which DCs can become licensed for cross-priming is through interaction with appropriatelyactivated CD4+ T cells. Licensing in this setting is mediated by the ligation of CD40 on the DCs by CD40L expressed on activated CD4+ T cells [43–45]. Evidence that this mechanism can operate in vivo was provided by studies comparing CD8+ T cell responses generated following injection of soluble ovalbumin (OVA) alone or OVA together with agonistic anti-CD40 antibodies [46]. While OVA alone failed to stimulate a productive response, OVA plus antiCD40 induced a strong OVA-specific CD8+ T cell response. However, priming of CD8+ T cell responses can occur in a CD40-CD40L-independent manner in the context of infection; this has been reported for various infectious agents, including HSV-1, influenza virus, VSV, LCMV and Listeria monocytogenes [47–51]. Although the specific contributions of cross-priming versus direct priming in these infections is unknown, it is clear that signals associated with infection can provide a stimulus for CD40/CD40Lindependent cross-priming. Notable examples of pathogen components that can promote cross-priming in this way include ligands of Toll-like receptor (TLR)3 and TLR9, which recognise dsRNA (indicative of viral infection) and immunostimulatory CpG DNA (present in the genomes of bacteria and DNA viruses), respectively [52,53]. As discussed below, IFN-a/b represents a host-derived, infection-induced signal that is able to induce cross-priming via a CD4+ T cell and CD40-independent pathway [54].

5. IFN-a/b IFN-a/b includes a large group of closely related cytokines that interact with a single IFN-a/b receptor

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(IFN-a/bR). IFN-a/b expression is induced rapidly by infection, particularly by viruses but also by bacteria. IFN-a/ b can be produced by virtually any cell type after infection, making it very effective at alerting the host to infection. Triggering of the IFN-a/bR induces a large number of genes that can ‘‘interfere’’ with viral replication or confer an antiviral state on uninfected proximal cells, which is crucial to the role of IFN-a/b in innate immunity [55]. Also, contributing to this innate defence function is the ability of IFN-a/b to activate the cytotoxic activity of cells such as macrophages and NK cells [56]. 5.1. Expression of IFN-a/b In recent years, great progress has been made in understanding the molecular mechanisms by which infection triggers expression of IFN-a/b. It is now clear that detection of conserved features of infectious agents by innate (germ-line-encoded) receptors plays a key role in this process. This is best characterised with respect to the TLRs; TLRs shown to induce IFN-a/b include TLR9 [57] (through recognition of CpG DNA), TLR3 [58] (dsRNA) and TLR7 [59–61], which functions in the recognition of viral ssRNA. Triggering of these receptors initiates a complex signalling cascade, involving the adaptor molecules Myd88 or TRIF, leading to the expression/activation of IRF3, IRF5 and IRF-7 [62]. In addition to TLRs, other innate sensing mechanisms have also been shown to initiate IFN-a/b expression. Of particular note are RIG-I and MDA5, cytosolic receptors which detect ssRNA [63,64]. The subcellular localisation of these latter receptors suggests that their main role is in sensing active infection. In contrast, the above mentioned TLRs, which function in endosomes, are likely to mediate recognition of pathogens that have been actively captured by a cell (either on their own or in the context of an infected cell). PDCs have been shown to be major producers of IFN-a/b in response to viral infection [20,65–67]. This is linked to their ability to produce much larger quantities of IFN-a/b on a per cell basis than most other cell types. Recently, this high IFN-a/b-producing capacity was demonstrated to be due to the ability of PDCs to retain TLR/Myd88/IRF-7 complexes in endosomes [68]; in other cell types such as conventional DCs, these complexes rapidly translocate to lysosomes. In this study, it was shown that conventional DCs could be turned into high IFN-a/b producers through enforced retention of such signalling complexes in endosomes [68]. Although PDCs may play a predominant role in producing IFN-a/b in response to certain infections, all cells seem to be capable of expressing at least some IFN-a/b after viral infection. Hence, the source of IFN-a/b is likely to vary depending on the tropism of the pathogen. Regardless of which cells produce IFN-a/b, it is clear that IFN-a/b is present in large amounts at an early stage after many types of infection, i.e. at a time when immune responses are initiated. As discussed below, the presence of

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IFN-a/b has an important influence on the immune response through direct effects on several immune system cells, including DCs, B cells and T cells.

6. Modification of DC function by IFN-a/b An ability of IFN-a/b to modify DC function has been reported in a number of different studies. This includes evidence that IFN-a/b may act very early to stimulate DC differentiation from human monocytes. Thus, it has been shown that monocytes cultured in GM-CSF + IFN-a/b rather than the more commonly used combination of GMCSF + IL-4, differentiate more rapidly into DCs. Moreover, IFN-a/b DCs were found to be more mature than IL-4 DCs, possessing a superior capacity to prime T cells in vitro [69,70] and an ability to promote humoral responses when pulsed with antigen and injected into humanized SCID mice [70]. However, by contrast with monocyte-derived (conventional) DCs, IFN-a/b is reportedly unable to promote the maturation of antigen-presenting ability of PDCs, although it does act as a survival factor for these cells [71]. In vitro treatment of immature conventional DCs (derived either from murine bone marrow precursors or human monocytes) with IFN-a/b has been shown to induce phenotypic maturation (upregulation of MHC Class I, class II, CD40, CD80, CD86, and higher expression of CD83 in the human system) [72–74]. These phenotypic changes are associated with a heightened capacity to induce naı¨ve T cell proliferation. Importantly, this is also true for in vivo generated DCs (blood DCs in humans [75] and splenic DCs in mice [72–74]. Moreover, injection of IFN-a/b into mice stimulates DC maturation in vivo [72–74]. Recently, IFN-a/ b induced after lymphocytic choriomeningitis virus (LCMV) infection of mice was shown to promote splenic DC maturation, although it also appeared to participate in the apoptosis of these cells triggered after this viral infection [67]. Aside from presentation of antigen and expression of appropriate levels of co-stimulatory molecules, a key requisite for DCs to stimulate a functional T cell response is their proper positioning within tissues. DCs must gain access to the T cell zones of secondary lymphoid organs in order to interact with naı¨ve T cells. Although some immature DCs are located in lymph nodes and spleen under steady state conditions, these cells are also found in large numbers in peripheral tissues at potential sites of pathogen entry, where they serve a sentinel function. Movement of DCs to lymphoid organs is dependent on upregulation of the chemokine receptor CCR7, which renders DCs sensitive to CCL19 and CCL21; these chemokines control DC exit from peripheral tissues and direct their migration towards the T cell area of lymphoid organs [76,77]. Induction of CCR7 expression is commonly associated with DC maturation, linking the receipt of infectious or danger signals with an ability to move to

locations where it is possible to initiate an immune response. In accordance with the notion that IFN-a/b is a DC maturation factor, upregulation of CCR7 has been observed following treatment of human DCs with IFN-a/b [78]. Interestingly, experiments in mice have also shown that IFNa/b is required for PDCs to migrate from the marginal zone into the T cell area where they form clusters [79]. Overall, it is evident that IFN-a/b has multiple effects on DCs, affecting their differentiation, maturation and migration.

7. IFN-a/b as a stimulator of cross-priming In view of its rapid expression in response to infection and ability to contribute to DC maturation, IFN-a/b seems well suited to a role as a licensing signal for cross-priming. Direct evidence that it can in fact function in this way came from studies in which the CD8+ T cell response to soluble OVA was studied in the context of a virus infection [54]. Administration of OVA protein, which can only stimulate a CD8+ T cell response by cross-priming, during the course of an LCMV infection was shown to induce efficient priming of OVA-specific CD8+ T cells. Importantly, no cross-priming against OVA was observed during infection with vaccinia virus, which unlike LCMV is a very poor inducer of IFN-a/ b, or when LCMV-infected IFN-a/bR-deficient mice were immunised. Thus, cross-priming in the context of an LCMV infection occurred by a mechanism that was dependent on IFN-a/b. Like viral infection, various TLR agonists have been shown to induce cross-priming, and the role of IFN-a/b in this context has also been investigated. Experiments using IFN-a/bR-deficient mice showed that cross-priming stimulated by TLR3 or TLR4 ligands was completely dependent on IFN-a/b, whereas that triggered by CpG DNA (TLR9) was partially reduced in mice lacking the IFN-a/bR [52,80]. Taken together, these results indicate that IFN-a/b is an important mediator in infection-stimulated cross-priming. Moreover, it has been shown that immunisation of uninfected mice with soluble OVA + recombinant IFN-a induces efficient cross-priming [54]. Thus, IFN-a/b appears to be sufficient to induce cross-priming in the absence of other infection-associated signals. Notably, IFN-a/b is able to induce cross-priming in both CD40-deficient mice and MHC class II-deficient (i.e., CD4+ T cell-deficient) mice, indicating that the CD40L-CD40 pathway of DC licensing is not involved in IFN-a/b-stimulated cross-priming. One factor contributing to the promotion of crosspriming by IFN-a/b is the stimulatory activity of this cytokine on DCs. This was demonstrated in experiments in which immunisation was accompanied by transfer of DCs into IFN-a/bR-deficient mice; the key finding was that IFNa/b was able to induce cross-priming in recipients of wildtype but not IFN-a/bR-deficient DCs [54]. In addition, there is also evidence that IFN-a/b licenses human DCs for crosspriming [81]. In this study, DCs generated from monocytes

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in the presence of GM-CSF plus IFN-a were superior to mature DCs generated under typical culture conditions (ie, GM-CSF plus IL-4) in stimulating cross-priming after transfer to humanised SCID mice. Exactly how exposure to IFN-a/b enhances the ability of DCs to induce cross-priming is unknown. Our unpublished studies have found no evidence that IFN-a/b augments antigen capture by mouse DCs (Le Bon and Tough, unpublished data). Similarly, DCs derived from human monocytes in the presence of IFN-a do not differ from DC generated with IL-4 in their capacity to internalise antigens [81]. IFN-a/b is able to stimulate increases in expression of TAP and cell surface MHC class I, implying that crosspresentation could be increased in response to IFN-a/b [80]. However, the available information suggests that any IFN-a/ b-induced increases in antigen presentation are minor. This conclusion is based on indirect data in which the level of antigen presentation in the presence or absence of IFN-a/b was compared by measuring the proliferation of TCR transgenic CD8+ T cells. Using this approach, it was found that DCs purified from mice injected with OVA + IFN-a stimulated only marginally greater proliferation of OVAspecific T cells (OT-I cells) than DCs obtained from mice injected with OVA alone [54]. Moreover, OT-I cells were observed to proliferate similarly in vivo after injection into mice given OVA alone or OVA plus IFN-a [82]. Therefore, it seems likely that IFN-a/b enhances the ability of DCs to cross-prime by augmenting their capacity to deliver secondary (co-stimulatory) signals rather than by boosting cross-presentation. As discussed above, IFN-a/b has been shown to increase expression of classical costimulatory molecules (CD80, CD86) on DCs, although it is unknown whether this is sufficient to license DCs for crosspriming. Interestingly, the enhanced cross-priming capacity of human DCs generated from monocytes in the presence of IFN-a/b was shown to correlate with increased expression of IL-23 and IL-27 [81]. Further work is required to define exactly what properties of DCs are essential for crosspriming and how these are affected by IFN-a/b. Although DCs represent one direct target of IFN-a/b, it is clear that enhancement of cross-priming by this cytokine is mediated through effects on other cell types as well. This was suggested from the finding that the cross-priming response generated after transfer of wild-type DCs into IFN-a/bbR-deficient mice was very low compared to that produced in normal animals even if the number of DCs injected was quite high [54]. Subsequent work, using mouse models in which T cells selectively lacked a functional IFNa/bR, demonstrated that optimal induction of crosspriming was dependent on the direct stimulation of T cells by IFN-a/b [82]. This finding was in accordance with that of another study, which showed that IFN-a/b stimulation of CD8+ T cells was required for productive clonal expansion of antigen-specific cells after LCMV infection [83]. Notably, direct effects on lymphocytes also appear to play a key role in other aspects of the immunostimulatory

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activity of IFN-a/b; IFN-a/b has also been shown to augment antibody responses [84], and direct effects on DCs, B cells and T cells all contribute to its activity [85]. Interestingly, direct effects of IFN-a/b on B cells seem to be crucial for the development of local humoral responses against viruses [86–88]. 8. Conclusions In addition to playing a vital role in innate anti-viral defence, IFN-a/b has important stimulatory effects on the adaptive immune response. Its ability to induce crosspriming provides one mechanism by which this type of immune response can be linked to the infectious process. At present, it is unclear to what extent cross-priming contributes to the generation of CD8+ T cell responses during viral infections; this is likely to be dependent on the specific tropism of the virus. Nevertheless, it seems plausible that there will be situations in which the majority of DCs presenting viral antigens will have acquired these by uptake of infected cells rather than through direct infection. Given that IFN-a/b represents a broadly expressed, rapidly inducible host response to infection, the sensitivity of various adaptive immune cells to this cytokine makes evolutionary sense. However, it should be pointed out that many viruses have evolved mechanisms to block the production or activity of IFN-a/b [89]. Although the primary benefit to these viruses may be in the inhibition of innate defence mechanisms, it is probable that ‘‘interfering with interferon’’ will also impact on the adaptive immune response. In keeping with this idea, the NS2 protein of respiratory syncytial virus was recently shown to suppress CTL responses through its ability to downregulate IFN-a/b [90]. As well as playing a role during natural infection, crosspriming may be exploited for vaccination. This could be particularly useful for vaccines where injection of live attenuated viruses carries a significant risk, or for cancer vaccines. Elucidating the mechanisms by which IFN-a/b stimulates cross-priming will help provide key information for the development of such novel vaccination strategies.

Acknowledgments Supported by the Marie Curie Action (Excellence grant), and the AVENIR program (INSERM).

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Agne`s Le Bon is currently a researcher at INSERM U591 at The Necker Institute in Paris, group leader of a Marie Curie Excellence Team and head of an AVENIR Team. Agne`s Le Bon received her PhD in Paris from the University Paris VI and completed her training with a first post doctoral position at the Scripps Research Institute and a second one at the Edward Jenner Institute in David Tough’s laboratory. In 2003, she became Career developement Fellow at the Edaward Jenner Institute and moved back to Paris in 2005. Her work has focused on studying in vivo immunological responses of both CD4 and CD8 T cells. David Tough is head of the T Cell Regulation group within the riCEDD at GlaxoSmithKline. Dr. Tough received his Ph.D. degree in Immunology from The University of Manitoba and completed post-doctoral training at The Scripps Research Institute. Prior to joining GSK in 2006, Dr. Tough was a Senior Group Leader at The Edward Jenner Institute for Vaccine Research. He has published extensively in the area of immunological memory and on the role of cytokines in initiating immune responses and controlling lymphocyte homeostasis. Dr. Tough is an Associate Editor for the Journal of Immunology and a member of the Medical Research Council College of Experts.