Antigen Presenting Cells and Molecular Mechanisms Underlying Induction of Immune Deviation

Sharmila Masli, J. Wayne Streilein,t and A. Paiman Ghafoori

Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, U.S.A.

INTRODUCTION

Immune privilege in the eye is known to protect the precious microanatomy of the visual axis from the inflammatory assault of an immune response, thereby avoiding any damage to accurate vision, while permitting expression of protective adaptive immunity. A fine balance between the protective and detrimental effects contributed by the immune system is maintained by the unique ocular microenvironment as well as specialized ocular cells. The peripheral adaptive immune responses to ocular antigens are directed by bone-marrow derived antigen-presenting cells (APCs) of the eye. Understanding mechanisms utilized by these cells to induce the unique immune response to ocular antigens is vital to the development of strategies to eliminate or avoid undesirable ocular immune responses. Analysis of such naturally existing mechanisms that avoid damaging immune responses also offers the opportunity to apply these mechanisms to generate therapeutic approaches to prevent inflammatory disease processes in non-immune privilege parts. Our current understanding of the mechanisms underlying antigen presentation as it relates to the induction of immune deviation is presented below.

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IMMUNE RESPONSE TO OCULAR ANTIGENS

Although many local factors contribute to a fine balance maintained in the eye between prevention of inflammation and promotion of immune protection, anterior chamber associated immune deviation (ACAID) represents an active phenomenon that induces a systemic effect that is involved in maintaining the immune-privileged status of the eye. Antigens introduced in the anterior chamber of an eye invoke a unique systemic immune response that is distinct from a conventional immune response. This immune response to ocular antigens differs from a conventional response in that it is deficient in pro-inflammatory (Th1) effectors and complement fixing antibodies (IgG2a) (1) that are potentially detrimental to the ocular tissue.

The systemic nature of ACAID was originally demonstrated when inoculation of F1 hybrid lymphocytes in the anterior chamber of parental strain recipients led to systemic suppression of cell-mediated immunity that allowed prolonged acceptance of orthotopic skin allografts (2). Similarly, tumor cells bearing minor antigens different from those of the recipient when injected into the anterior chamber prevented subsequent rejection of a skin graft expressing those minor antigens (3,4). This failure to reject allografts correlated with the absence of alloantigen-specific delayed type hypersensitivity (DTH) response. Such immune deviation was also transferable to naïve recipients via adoptive transfer of spleen cells (5). This systemic effect was antigen specific. Paradoxically, presence of alloantibodies and alloantigen-specific cytotoxic T cells further underscored the uniqueness of the systemic immune response to eye-derived antigens. More recently it was demonstrated that when a soluble antigen such as ovalbumin is injected in the anterior chamber of an eye, ovalbumin-specific cytotoxic cells are inhibited (6).

EYE-DERIVED APCs

During the analysis of mechanisms responsible for the immune privilege property of the eye it was determined that bone marrow-derived cells in the iris and ciliary body of the anterior chamber exhibit immunoregulatory properties in that these cells not only failed to stimulate allogeneic lymphocytes but also suppressed mixed lymphocyte reaction (7). These bone marrow-derived cells predominantly expressed F4/80 marker and about one third of these cells expressed CD11b/Mac-1. Detection of such cells expressing markers typically present on macrophages suggested a possibility of their role in antigen presentation that results in a unique immune response to antigens introduced in the eye. Further, in the absence of lymphatic drainage of the eye, antigen-bearing cells were postulated to leave the eye via the blood to induce a systemic immune response. Accordingly, antigen-specific cells capable of inducing immune deviation were detected in the peripheral blood of animals receiving that antigen in their anterior chamber (8). These cells expressed F4/80 and were believed likely to be eye-derived since antigen introduced at sites other than anterior chamber did not release such cells into the peripheral circulation. Presence of cells capable of transferring immune deviation in the spleens of mice receiving anterior chamber inoculation of an antigen suggested the spleen to be the likely destination of the F4/80 expressing cells that exited the eye. While F4/80-expressing cells derived from the peritoneal cavity were found to uniquely localize to the spleen when treated with ocular tissue-derived factors, more recently such cells were reported in the marginal zone of the spleen in aggregates of T and NKT cells (9). Thus, local F4/80 expressing APCs of the iris and ciliary body are believed to carry antigen via the blood to the spleen where their interactions with lymphocytes leads to the generation of regulatory cells that actively maintain the unique peripheral response to antigens introduced in the eye. Recently, the long-held view of a lack of lymphatic drainage in the eye has been re-evaluated and the existence of lymphatic drainage available to ocular antigens was documented (10). Moreover, tracking of fluorescently labeled antigens introduced in the anterior chamber of an eye revealed the presence of this antigen in the secondary lymphoid organs such as the submandibular lymph nodes and cervical lymph nodes as well as the spleen. The antigen-bearing cells were predominantly macrophages.

Similar to resident ocular F4/80+ cells from the normal iris and ciliary body, extraocular F4/80+ macrophages acquire the ability to induce immune deviation when exposed to the ocular environment upon their injection into the anterior chamber (11). Such acquisition of this unique ability to induce immune deviation is also possible in vitro by exposure of F4/80+ macrophages to aqueous humor or culture supernatants from cells largely responsible for aqueous humor production, i.e., iris and ciliary body (12). The ability to alter the functional phenotype of F4/80+ macrophages is attributed to intraocular TGF^. This well-known immuno-suppressive cytokine is present in abundance in the aqueous humor and is also produced by the parenchymal cells of the iris and ciliary body.

CHARACTERIZATION OF EYE-DERIVED APCs

In vitro exposure of F4/80+ cells from the peritoneal exudate to TGF^ renders them capable of inducing immune deviation similar to that induced by eye-derived APCs (13). Such TGF^-treated peritoneal exudates cells (PECs) when pulsed with heterogeneous antigens such as ovalbumin (OVA) can stimulate OVA-specific T cells in vitro in a manner that prevents the synthesis of inflammatory cytokines such as IFN-y thereby disabling their Th1 type pro-inflammatory activity (14). Further, these T cells exhibit properties similar to those expressed by regulatory T cells detected in the spleens of mice that receive anterior chamber inoculation of the antigen (15). Similar to in vivo generated regulatory cells, T cells co-cultured with TGF^-treated APCs suppress both the induction and expression of delayed type hypersensitivity response (15,16). Therefore, analysis of TGF^-treated APCs provided insights into mechanisms utilized by eye-derived APCs during antigen presentation. Exposure to TGF^ impairs the ability of APCs to express accessory molecules (IL-12, CD40) important in the induction of a conventional immune response (17). These APCs begin to synthesize other immunomodulatory cytokines such as IL-10 and type I IFN (18,19). Also, TGF0-exposed APCs produce increased amounts of active TGF0, which in turn can influence APCs in an autocrine or paracrine manner and allow amplification of the original TGF0 effect (14). Expression of chemokines such as MIP-2 was also found to be increased in TGF0-treated APCs (9,19). It was further determined that this chemokine permits recruitment of innate cells such as NKT cells to the marginal zone of the spleen where APCs present antigens to T cells and are engaged in inducing a regulatory cell population that imparts the systemic effect resembling peripheral tolerance (20). Along with marginal zone B cells and NKT cells, TGF0-treated APCs create a microenvironment that is conducive to the generation of regulatory T cells. This microenvironment is rich in immunosuppressive cytokines such as IL-10 and TGF0. Thus, ocular APCs are believed to create a TGF0-rich environment away from their origin and allow the generation of regulatory cells.

MOLECULAR MECHANISMS UNDERLYING ANTIGEN PRESENTATION BY EYE-DERIVED APCs

Impaired expression of IL-12 has become a prototypic property of tolerogenic APCs. Functional characteristics of TGF0-treated APCs are consistent with such tolerogenic APCs because TGF0 exposure of conventional APCs confers upon them the ability to generate regulatory cells that suppress systemic Th1-mediated immune responses, such as DTH. The absence of a pro-inflammatory cytokine such as IL-12 appears to be critical in the induction of immune deviation by eye-derived APCs in that its absence aborts differentiation of antigen-specific T cells activated by these APCs down the Th1 pathway (21). Development of Th1 effectors is restored by the addition of exogenous IL-12 in the anterior chamber along with the antigen. Therefore TGF0 exposure of APCs is likely to induce pathways that downregulate their IL-12 expression, which in turn contributes to their unique ability to induce immune deviation. In TGF0-treated APCs, one indicator of such a possibility of IL-12 regulation was their decreased expression of CD40, a molecule known to induce IL-12 synthesis upon its ligation by corresponding CD40L on activated T cells.

Comparison of the transcriptional programs of APCs exposed to TGF0 with that of untreated APCs by microarray analysis offered an opportunity to examine candidate molecules that support the ability of APCs to induce immune deviation. Such analysis revealed increased expression of molecules that contribute to down-regulation of IL-12. These included thrombospondin (TSP), TNFR II(p75), and IkBo: (19). To analyze the significance of these molecules as it relates to the induction of immune deviation, we assessed involvement of these molecules in the regulation of IL-12 synthesis and subsequent suppression of DTH response by TGF0-treated APCs.

Thrombospondin

Of the five known isoforms of this extracellular matrix (ECM) protein, TSP1 synthesis was upregulated in TGF^-treated APCs. This ECM protein is a large (450 kD) molecule with multiple functional domains that allow its binding to various receptors such as CD47, CD36, av^3, heparan sulfate, and integrins (22). Such ability to bind different receptors provides a functional diversity to TSP1 that depends on the effect of its binding to these receptors on various cells and subsequent signaling induced within these cells. For instance, the anti-angiogenic effect of TSP1 is attributed to its ability to bind CD36 on vascular endothelium and the resulting apoptosis of these cells (23,24). The extensively analyzed property of TSP1 to activate latent TGF^ has been associated with its binding of CD36 on macrophages (25). More recently, ligation of CD47 by TSP1 on monocytes and macrophages was reported to inhibit secretion of IL-12 (26,27). Similarly, such CD47 ligation was reported to prevent maturation of dendritic cells as well as block their ability to generate Th1 effectors (28). Consistent with these observations, TSP1 in TGF^-treated APCs contributes to both the activation of latent TGF^ as well as regulation of IL-12, as APCs are known to express both CD36 and CD47 (29). Ligation of CD47 on T cells has been demonstrated to induce signals that influence TCR-mediated signaling events and therefore are known to alter T cell activation (30,31). It was also proposed that by binding CD47 and CD36 on different cells TSP could provide a trimolecular bridge between those cells. Therefore, it appears possible that TGF^-treated APCs utilize a multifunctional molecule such as TSP to tether latent TGF^ on their cell surface via their CD36 receptor such that active TGF^ is made available in the microenvironment. Thrombospondin may also regulate their IL-12 secretion via CD47 ligation, and, furthermore, APCs may also use CD36 bound TSP to bind CD47 on effector T cells, influencing their TCR mediated signals in a way that leads to generation of regulatory cells rather than Th1 type. In the absence of TSP, APCs treated with TGF^ failed to induce immune deviation (29). Therefore, TSP-mediated molecular mechanisms employed by eye-derived APCs are critical for their ability to induce immune deviation.

TGF^-treated APCs increase their expression of TNFR II. These APCs also synthesize and release increased levels of TNF-a32. Contrary to its traditional pro-inflammatory role, TNF-a is essential for the induction of immune deviation as anti-TNF-a antibodies injected at the time of anterior chamber inoculation of an antigen or after intravenous injection of antigen-pulsed TGF^-treated APCs prevents suppression of the DTH response (32,33). Such an anti-inflammatory role of TNF-a was originally suggested in TNF-a-deficient mice, as their homeo-static regulation of inflammation was impaired (34). In these mice a role for TNF-a in limiting the inflammatory response was implicated. Such a role was later demonstrated to be effective through TNF-a-mediated regulation of IFN-y-induced IL-12 secretion in macrophages (35). Similarly, it is quite likely that TNF-a released by TGF^-treated APCs contributes to its impaired ability to secrete IL-12. The inability of TNF-a deficient APCs to induce immune deviation or inhibit IL-12 secretion after their TGF^ treatment supported such a possibility (36). The pro-inflammatory effects of TNF-a are primarily associated with signals mediated via TNFR I (p55); however, whether TNFR II (p75) is likely to induce anti-inflammatory signals is not yet clear (37). The difference between the two TNF receptors in their affinity for TNF-a is well established. It is also reported that the receptor with higher affinity for TNF-a, i.e.,TNFR II, is inefficient at activating the pro-inflammatory transcription factor NFkB as compared to TNFR I (38). Such a difference raises the possibility that signals mediated through TNFR II may contribute to anti-inflammatory effects. This possibility is further strengthened by increased expression of TNFR II in TGF^-treated APCs that are capable of suppressing inflammatory DTH response. This increase in the TNFR II is significant to their immune deviation-inducing property as its absence prevents APCs from undergoing functional transformation in response to TGF^ (36). Assessment of the significance of this TNFR II in the ability of TGF^-treated APCs to induce immune deviation indicates that TNF-a synthesized by these APCs contributes to regulation of IL-12 via TNFR II and thereby exerts its anti-inflammatory effect.

iKBa

Transcription factor NFkB proteins are present in the cytoplasm associated with the inhibitory I KB proteins. Binding of IkB proteins is known to mask the nuclear localization signal (NLS) of NFkB proteins thereby preventing their access to the nucleus (39). Phosphorylation of IkB proteins initiates their dissociation and degradation, allowing nuclear translocation of NFkB proteins. In the nucleus NFkB proteins bind their cognate DNA binding sites to regulate transcription of a large number of genes that include pro-inflammatory molecules such as CD40 and IL-12. Therefore, activation of the NFkB pathway is associated with inflammatory processes. In dendritic cells it was also demonstrated that antigen presentation is dependent on NFkB activation and that different aspects of this process, such as MHC and co-stimulatory molecule expression, as well as cytokine production, are coordinately regulated (40,41). Inhibitory IkB proteins are known to interrupt the NFkB pathway, and therefore inflammatory signals, by avoiding the NFkB-mediated transcription of genes. This is accomplished by either retaining NFkB proteins in the cytoplasm or by dissociating DNA-bound NFkB in the nucleus. Newly synthesized IKBa proteins have an intrinsic NLS that allows their entry into the nucleus, displacement of NFkB from its DNA binding sites, and transport of NFkB back to the cytoplasm (39). Increased expression of IKBa in TGF^-treated APCs is consistent with their impaired expression of NFKB-regulated pro-inflammatory molecules such as CD40 and IL-12. Therefore, IL-12 synthesis in TGF^ exposed APCs is likely to be impaired due to inhibition of a transcription factor, NFkB, associated with its synthesis. Blocking synthesis of iKBa in TGF^-treated APCs using an RNA interference strategy allowed us to examine the significance of this regulatory protein in the induction of immune deviation (42). Results from our studies allowed us to conclude that TGF^ exposure of APCs prevents transcription of pro-inflammatory genes, presumably by inhibiting the transcriptional activity of NFkB.

SUMMARY

The unique immune response to eye-derived antigens is attributed to functionally specialized resident APCs. These APCs induce immune deviation, a form of peripheral tolerance, which contributes to the immune privilege status of the eye by generating regulatory cells in a secondary lymphoid organ such as the spleen. TGF^ in the ocular microenvironment confers the ability to induce immune deviation on APCs. These APCs suppress peripheral Thl-mediated immune responses such as DTH, which is accomplished by multiple molecular mechanisms invoked under the influence of TGF^. By lowering their expression of pro-inflammatory molecules such as CD40 and IL-12, these APCs avoid inflammatory immune responses while increased expression of molecules such as thrombospondin, TNFR II, and IKBa contributes to anti-inflammatory effects by helping maintain lowered IL-12 expression. Thrombospondin also allows activation of latent TGF^ tethered to the cell surface, thereby providing an immunosuppressive microenvironment that resembles the ocular microenvironment. These mechanisms allow eye-derived APCs to avoid pro-inflammatory effects while promoting anti-inflammatory effects giving rise to immune deviation.

ACKNOWLEDGMENT

Some of the research reported in this communication has been supported by National Institute of Health grant EY013775.

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