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Originally published online as doi:10.1189/jlb.1102544 on May 22, 2003

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(Journal of Leukocyte Biology. 2003;74:172-178.)
© 2003 by Society for Leukocyte Biology

Corneal immunity is mediated by heterogeneous population of antigen-presenting cells

Pedram Hamrah, Syed O. Huq, Ying Liu, Qiang Zhang and M. Reza Dana

Laboratory of Immunology, Schepens Eye Research Institute, and the Massachusetts Eye & Ear Infirmary and the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts

Correspondence: Dr. M. Reza Dana, Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114. E-mail: dana{at}vision.eri.harvard.edu


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ABSTRACT
 
Corneal antigen-presenting cells (APC), including dendritic cells (DC), were thought to reside exclusively in the peripheral cornea. Here, we present recent data from our group demonstrating that the central cornea is indeed endowed with a heterogeneous population of epithelial and stromal DC, which function as APC. Although the corneal periphery contains mature and immature resident bone marrow-derived CD11c+ DC, the central cornea is endowed exclusively with immature and precursor DC, both in the epithelium and the stroma, wherein Langerhans cells and monocytic DC reside, respectively. During inflammation, a majority of resident DC undergo maturation by overexpressing major histocompatibility complex class II and B7 (CD80/CD86) costimulatory molecules. In addition to the DC, macrophages are present in the posterior corneal stroma. In transplantation, donor-derived DC are able to migrate to host cervical lymph nodes and activate host T cells via the direct pathway when allografts are placed in inflamed host beds. These data revise the tenet that the cornea is immune-privileged as a result of lack of resident lymphoreticular cells and suggest that the cornea is capable of diverse cellular mechanisms for antigen presentation.

Key Words: corneal stroma • dendritic cells • macrophages • major histocompatibility complex • corneal transplantation


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INTRODUCTION
 
In 1868, the medical student Paul Langerhans discovered a population of dendritic cells (DC) in the suprabasal regions of the skin epidermis that are now eponymously referred to as Langerhans cells (LC) [1 ]. LC are now known to be major histocompatibility complex (MHC) class II (murine Ia)-expressing bone marrow (BM)-derived epidermal DC [2 ]. The cardinal properties of DC include their ability to migrate selectively through tissues; take up, process, and present antigen; and stimulate and direct T lymphocyte-dependent responses. DC are comprised of a heterogeneous group of "professional" BM-derived antigen-presenting cells (APC), which include members of different lineages and states of maturation [3 ]. The diverse functions of DC in immune regulation depend on the diversity of DC subsets and lineages and on the functional plasticity of DC at their immature stage. Immature DC are characterized by a high capacity for antigen capture and processing but a low T cell-stimulatory capability [4 ]. The immature DC have a low-to-negligible amount of MHC class II expression and lack the requisite accessory (costimulatory) signals for T cell activation, such as CD40, CD80 (B7-1), and CD86 (B7-2) [2 ]. Maturation of DC renders these cells poor in antigen capture but potent in T cell stimulation. In addition to the immature DC, proliferating stem cells also give rise to nonproliferating DC precursors in the blood, which express the myeloid antigens CD11b and CD11c [5 ].


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DC OF THE CORNEA
 
The cornea is the clear, avascular tissue of the anterior part of the eye. It is divided into three layers, each of which plays a role in keeping it transparent: the outer, multicellular epithelial layer; the middle, dense, connective tissue-stromal layer, which forms ~90% of the tissue’s thickness; and the inner, endothelial, single-cell layer. Under nonpathological circumstances, LC are the only cells that constitutively express MHC class II molecules in the corneal epithelium [6 ]. Over the last several decades, the search for corneal APC, largely reliant on their presumed and universal MHC class II expression, has led to the dogma that LC are present only in the epithelium of the conjunctiva and peripheral third of the cornea but are absent in the central cornea [7 8 9 10 ], although isolated MHC class II+ or CD45+ cells had been observed in the center of the normal cornea [11 12 13 ]. It is, however, generally acknowledged that a number of corneal stimuli, including, infection, trauma, and cauterization, result in the presence of MHC class II+ DC in the central cornea, which was, until recently, presumed to be entirely a result of de novo infiltration of these cells into the cornea [14 15 16 ].

There have been important biological implications for the now-disproved contention that the normal cornea is devoid of a DC population. For example, the putative lack of a normal endowment of DC in the cornea has led many investigators to propose that the priming of recipient T cells in corneal transplantation relies exclusively on host APC through the indirect pathway of sensitization [14 , 17 ]. This is in contrast to other forms of solid organ transplantation, where graft-borne "passenger leukocytes" play an important role in directly sensitizing host T cells by the concomitant expression of donor MHC and antigens [18 ]. In addition to their role in transplantation, the number and activity of corneal DC have been associated with the induction and amplification of immunoinflammatory responses in microbial keratitis [19 , 20 ]. Here, we review recent data from our laboratory, which have profoundly revised the paradigm of corneal DC recruitment and function, and demonstrate that the central cornea is indeed endowed with a heterogeneous population of epithelial and stromal APC [21 22 23 24 25 ], in addition to macrophages that were recently identified by Hendricks and co-workers [26 ] independently in the normal stroma.


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MHC CLASS II-NEGATIVE LC IN THE CORNEAL EPITHELIUM
 
We have examined whole-mounted epithelial sheets of uninflamed corneas using selective antibodies [21 ]. Initial screening by staining epithelial sheets for CD45 (leukocyte common marker) and CD11c (DC/LC marker) demonstrates that the peripheral and central areas of the epithelium are endowed with large numbers of BM-derived cells, and the density of these cells decreases from the limbus toward the center. Although a large number of DC are MHC class II+ in the periphery (Fig. 1A and 1B ), the corneal epithelium is endowed with a large population of MHC class II-negative LC in the periphery and the center of the epithelium, and the center is exclusively MHC class II-negative (Fig. 1C) . All CD45- and CD11c-labeled cells have the classic DC morphology of LC, as shown at higher magnifications, and are uniformly negative for B7 (CD80 or CD86) costimulatory molecules, CD11b, and CD3. Our results are confirmed by transmission electron microscopy of the epithelium, demonstrating the presence of numerous DC with long processes interdigitating among the corneal epithelial cells, containing the LC-specific Birbeck granules. MHC class II-negative LC have also been described in the skin [27 28 29 30 ]. A comparison between CD1a and MHC class II antigen expression, which is possible in the skin, is, however, not possible in the corneal epithelium, as corneal LC do not express the CD1a antigen [31 ].



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  		Figure 1. MHC class II-negative LC in the center of the corneal epithelium. Confocal micrographs of MHC class II (A) and CD45 (B) double-stained, whole-mounted corneal epithelial sheet demonstrate LC throughout the cornea. The density decreases from the limbus (lower-right corner) toward the center of the cornea (upper-left corner; B). The same cells are MHC class II-positive in the limbus and periphery of the cornea but not in the paracentral and central areas (A). Confocal micrograph of the center of the cornea shows CD11c+ LC (C). CD11c expression of these cells in the center of the cornea provides evidence that they are of DC lineage in addition to the typical dendritic morphology. These LC in the center do not express MHC class II antigens. Original magnification: (A, B) x160; (C) x1000. Adapted from ref. [21 ].


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APC POPULATIONS IN THE STROMA
 
We have systematically examined the corneal stroma for DC and have characterized the lymphoreticular populations in the stroma [22 ]. Staining reveals the presence of significant numbers of CD45+CD11c+CD11b+CD8{alpha}- DC in the periphery and center of the anterior stroma, therefore demonstrating myeloid DC from a monocytic lineage. Further staining reveals that a population of these stromal DC is MHC class II+ and positive for costimulatory markers CD80 (Fig. 2A and 2B ), CD86, and CD40 in the periphery. The stromal center, however, contains exclusively MHC class II-CD80-CD86- DC (Fig. 2C and 2D) , similar to findings of immature LC in the epithelium, and the density of stromal DC decreases from the limbus toward the center.



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  		Figure 2. Immature/precursor DC in the anterior corneal stroma. Double-staining with CD11c (A) and CD80 (B) shows that all CD80+ cells are BM-derived CD11c+ DC and demonstrates CD11c+ CD80- DC throughout the cornea. The density decreases from the limbus (left) toward the center of the cornea (right). However, CD11c+ cells (C) do not express MHC class II (D) or B7 costimulatory molecules in the center of uninflamed cornea. Original magnification: (A, B) x160; (C, D) x400. (A, B) adapted from ref. [22 ].

In addition to the CD11c+CD11b+ DC in the anterior stroma, a population of CD11c-CD11b+ cells is present in the posterior stroma (Fig. 3A ). Although the CD11c+CD11b+ cells in the anterior stroma have a dendritic morphology, CD11c-CD11b+ cells in the posterior stroma have a morphology resembling macrophages (Fig. 3B) . These cells most probably correspond with macrophages that were recently described by Brissette-Storkus et al. [26 ] in the normal corneal stroma. Furthermore, corneas stained for CD14, an "immature" cell-surface marker reported to be associated with lack of differentiation of DC, demonstrate a large number of CD14+ cells in the stroma, a population distinct from the CD11c+ DC described above, which are CD14dim or CD14-. These cells are further MHC class II-B7-CD40-GR-1-CD3-, and their number is by far larger than the number of CD11c+ or CD11b+ cells, indicating a population of undifferentiated monocytic precursor cells distinct from DC and macrophage populations described above. The presence of undifferentiated precursor DC would be similar to the recent finding of DC precursors in the central nervous system (CNS) [32 ], where these cells can be skewed toward a DC or macrophage-like profile in response to different factors. Thus, in contrast to other organs, where terminally differentiated populations of resident DC and/or macrophages outnumber colonizing precursors, large numbers of DC within the cornea remain in an undifferentiated state.



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  		Figure 3. Monocytes/macrophages are localized in the posterior stroma. Stacked sections of the stroma demonstrate CD11c-CD11b+ monocytes/macrophages in the posterior stroma (A). At higher mignification, CD11c-CD11b+ cells in the posterior stroma have a morphology that resembles macrophages (B). Original magnification: (A) x400; (B) x1000. Adapted from ref. [22 ].

Our results that were obtained from BALB/c mice have also been confirmed in other strains of mice and are therefore not strain-specific. Our in vivo results are further confirmed by an in vitro data based on harvesting adherent (macrophages) and nonadherent cells (DC) in culture and by flow cytometry. In the aggregate, the constitutive presence of these cells in the cornea focuses attention on the cornea as a participant in immune and inflammatory responses rather than the cornea being essentially a collagenous tissue that simply responds to the activity of infiltrating cells.


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RESIDENT CORNEAL DC IN INFLAMMATION
 
After the discovery of resident LC in the epithelium and monocytic DC in the stroma, we undertook experiments to determine how the distribution, phenotypes, and maturation states of stromal and epithelial DC are altered in inflammation. Application of electric cautery to the ocular surface is a standard method of inducing corneal inflammation [15 , 33 , 34 ]. Corneas were excised at different time points after cautery, the epithelium removed, and the epithelium or stroma examined separately. As early as 24 h after inducing inflammation, a subset of DC and LC in the center of the cornea expresses MHC class II, whereas paracentral areas away from the cautery sites remain MHC class II-, suggesting up-regulation of this marker in resident DC. By days 3 and 7, these paracentral sites also contain MHC class II+ cells. In inflamed corneas, surface expression of CD80 and CD86 is similarly increased for peripheral DC and is also present on DC in the central areas of the stroma (Fig. 4A and 4B ) and on LC in the central epithelium.



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  		Figure 4. Corneal DC express maturation markers in the center of the stroma and epithelium in corneal inflammation. In inflamed eyes, increased numbers of CD11c+ cells are seen in the corneal center (A), with many coexpressing B7 costimulatory markers (B) and MHC class II. Corneal transplantation was performed using C57BL/6 (Iab) mice as donors and BALB/c (Iad) mice as recipients. Although at 12 h post-transplantation, the grafted cornea does not express donor MHC class II (C), the central donor cornea exhibits donor-type MHC class II-positive cells as early as 24 h after transplantation near the graft-host border (D). Original magnification: (A, B) x400; (C, D) x160.

Experiments using the corneal transplantation model similarly confirm the maturation of resident corneal DC. These experiments confirm that the surface expression of MHC class II and B7 costimulatory molecules in inflammation is largely through up-regulation by resident cells and clearly not solely a result of influx of new leukocytes. Staining for donor-type MHC class II of C57BL/6 mice (Iab) at different time points after corneal transplantation into BALB/c (Iad) recipients shows that resident DC in the donor button of the grafted corneas are MHC class II- at 12 h after surgery (Fig. 4C) . Although corneas do not stain for MHC class II immediately after grafting, by 24 h after transplantation, novel donor class II (Iab) expression can be detected close to the graft-host junction (Fig. 4D) . At the early time points, when no staining for donor MHC class II is detected, a centrifugal migration of MHC class II- DC toward the graft-host border is seen. To better understand the dynamics of stromal DC and epithelial LC in normal versus inflamed corneas, a conceptual model is provided in Figure 5 .



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  		Figure 5. DC phenotype in normal and inflamed corneas. A conceptual model for BM-derived cells in the normal versus inflamed cornea shows MHC class II+ B7+ mature CD11c+ DC in the stromal periphery and Ia- B7- immature or precursor DC in the corneal center. Similarly, the epithelium contains MHC class II+ but B7- LC in the periphery and MHC class II-B7- LC in the epithelial center. In addition, the posterior stroma contains a population of macrophages. The inflamed cornea becomes endowed with significantly more mature DC and macrophages in the center.

The release of proinflammatory cytokines, including interleukin (IL)-1ß, granulocyte macrophage-colony stimulating factor, tumor necrosis factor (TNF)-{alpha}, as well as CD40L and lipopolysaccharides or heat-shock protein from dying cells, creates a microenvironment that activates immature DC, including LC [2 , 35 36 37 38 39 ]. Infection and inflammation likewise stimulate the release of a variety of chemokines, which promote the recruitment of DC precursors [2 ]. DC are also important producers of type 1 interferons (IFNs), TNF-{alpha}, and IL-1ß, which can act in an autocrine manner to promote DC activation and maturation [40 ]. Previous studies from our group have shown that suppressing IL-1 or TNF-{alpha} suppresses LC migration in the corneal epithelium [34 , 41 ]. These are in accord with previous data from our group demonstrating the central roles of IL-1 and TNF-{alpha} in corneal inflammation and transplantation immunity [42 43 44 45 46 ]. In these studies, we had shown that suppressing IL-1 or TNF-{alpha} can significantly suppress LC migration into the corneal epithelium and proposed that this is a principal mechanism by which immunity in the cornea can be regulated. However, in light of the recent data presented herein, it is possible that an additional mechanism by which suppression of these cytokines can down-modulate corneal immunity is by suppressing the maturation of resident epithelial LC and/or stromal DC in addition to suppressing the recruitment of de novo cells into the cornea. So far, very little is known about the molecular mechanisms that suppress DC maturation or retain DC in an immature state. Several candidates include prostaglandin E2 (PGE2) and cytokines such as transforming growth factor-ß and IL-10, which are known to have a profound capacity to down-regulate MHC class II expression [47 48 49 ]. Studies have demonstrated that the corneal endothelium produces basal levels of endogenous PGE2 [50 ]. So, it is enticing to postulate—although we do not have data definitely confirming it at this time—that the cornea may be involved in regulating immunity by active suppression of resident DC maturation.


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RESIDENT CORNEAL DC MIGRATE TO DRAINING LYMPH NODES
 
Solid organ grafts (e.g., heart, kidney, and skin) are significantly endowed with MHC class II+ DC [4 , 51 , 52 ] capable of migrating to host lymphoid organs and stimulating T cells directly by presenting donor-derived peptides in the context of donor MHC class II [51 , 53 ]. As a result of the putative absence of corneal BM-derived APC, allosensitization in corneal transplantation was previously thought to rely exclusively on the indirect pathway [54 , 55 ]. To evaluate whether host resident MHC class II-negative DC are able to migrate to host draining lymph nodes (LN), transgenic green fluorescent protein (GFP) or C57BL/6 (Iab) mice were transplanted into BALB/c (Iad) hosts [23 ], and corneas were examined post-transplantation. At 24 h (or later) after transplantation, GFP+ cells migrated centrifugally out into the wild-type recipient beds (Fig. 6A ). LN that were harvested at various time points after corneal transplantation demonstrated that there is ample traffic of donor MHC class II+ cells to host draining LN (Fig. 6B) and that these donor MHC class II+ cells colocalized strongly with GFP expression.



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  		Figure 6. GFP+ resident donor DC are evident migrating centrifugally out of the cornea into the draining LN of hosts. Confocal microscopic analysis performed on transgenic GFP+ grafts placed onto wild-type hosts (shown as black background) revealed migration of donor-derived GFP+ cells into the recipient bed (A). Cervical LN from BALB/c hosts grafted with C57BL/6 background mice immunostained for detection of donor MHC class II (Iab) demonstrated donor-type Iab cells in LN (B). Dashed line demarcates the graft-host margin; *, GFP+ cells. Original magnification: x400. Adapted from ref. [23 ].


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CORNEAL DC CAN FUNCTION AS APC AND SENSITIZE HOSTS VIA THE DIRECT PATHWAY IN HIGH-RISK CORNEAL TRANSPLANTATION
 
The evidence for resident corneal MHC class II- DC capable of trafficking to draining LN as more mature MHC class II-expressing cells raised the question of the allostimulatory capacity of these cells. Harvested corneal cells used as stimulators in mixed lymphocyte reaction assays with allogeneic responder splenic cells demonstrate that cultured allogeneic corneal cells have a modest allostimulatory capacity [23 ]. However, the stimulatory capacity of these corneal cells is significantly lower than that observed for allogeneic splenic controls. To test whether corneal DC can sensitize T cells directly, two models of corneal transplantation were used. In one model, C57BL/6 donor grafts were placed onto uninflamed [low-risk (LR)] BALB/c beds; in a second model, donor grafts were placed onto inflamed [high risk (HR)] beds [25 ]. Responder cells, harvested from LR and HR recipients at 14 days postkeratoplasty from LN ipsilateral to the grafted eyes, were used to measure the alloresponses in enzyme-linked immunospot assays. Splenocytes obtained from donor and recipient naïve mice served as a source of allogeneic or syngeneic stimulator cells, respectively. Irradiated donor-type APC were incubated with the T cells purified from the cervical LN, and the frequency of T cells producing IL-2 and IFN-{gamma} was then measured. As seen in Figure 7 , T cells of HR graft recipients, when compared with LR recipients and naïve controls, produce significant levels of IL-2 and IFN-{gamma}. The data demonstrate that directly primed, alloreactive T cells are in fact elicited by corneal grafts placed onto inflamed HR beds, emphasizing that the dominant role played by the indirect pathway of sensitization, when grafts are placed onto uninflamed host beds (LR transplantation) [56 ], should not be understood as an exclusive one. Therefore, there is evidence that the direct and indirect pathways of sensitization may concur in corneal transplantation, similar to what has been demonstrated in other organ grafts such as the skin [57 ], and the relative contribution of each pathway is based on multiple host- and time-dependent factors.



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  		Figure 7. The indirect and the direct pathways are involved in HR corneal transplantation. IL-2 and IFN-{gamma} production by T cells isolated from draining cervical LN are shown 2 weeks post-LR and -HR keratoplasty. As is shown by the graphs, T cells activated via the direct pathway of allosensitization produce significant levels of both these typical type 1 cytokines in the HR group when compared with LR and naïve responder cells (**, P<0.01). As expected, very little type 1 direct-response is detected in the LR transplantation setting. Syn, syngeneic; Allo, allogeneic.


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IMPLICATIONS
 
The constitutive presence of DC/APC in the cornea has significant implications for a variety of pathological and immunoinflammatory responses in the ocular anterior segment, including alloimmune, autoimmune, and innate-immune responses. Specifically in transplantation, as the presence of resident corneal DC was unknown until very recently, many investigators had proposed that priming recipient T cells in transplantation relies almost exclusively on the indirect pathway of sensitization. Our findings now focus attention on the cornea as a participant in immune and inflammatory responses, rather than the cornea being a tissue that simply responds to the activity of infiltrating cells. Our data would suggest that under certain conditions, the activation of these resident corneal DC leads to direct presentation of graft antigens to host T cells. Likewise, the pathobiology of stromal wound-healing has only been related to stromal keratocyte and matrix responses to infiltrating leukocytic populations. As it is known that DC can have an important role as mediators of innate immunity and given the contribution of inflammatory cytokines to stromal wound-healing, it is important now to critically evaluate the possible role of these cells in stromal wound-healing as well. Further, macrophages that were found in the posterior stroma [22 , 26 ] express low amounts of MHC class II and thus can play a role in antigen presentation in secondary immune responses, but resident tissue macrophages are in general poorly responsive to activation signals. They are professional phagocytes and play a pivotal role as effector cells in cell-mediated immunity and inflammation and in other processes including immune regulation, tissue reorganization, and angiogenesis [58 ].

To better understand the implications of our data for clinical conditions, preliminary experiments using the human cornea were started that demonstrate the presence of human leukocyte antigen-DR+ dendritiform cells in the periphery of the human cornea but are not phenotyped as thoroughly as in mice. Detailed phenotyping of the human cornea requires extensive experimentation with freshly procured tissues (as placing tissues in culture leads to migration of DC from the explants) from healthy donors, a difficult task that has not been completed by us. Better understanding of the mechanisms that lead to DC maturation and activation in the cornea may lead to novel approaches in the induction of tolerance in transplantation, autoimmunity, and allergy. Further studies are required to determine the molecular mechanisms that regulate the maturation of these cells and their immunobiologic phenotype in stimulating or tolerizing T cells generated in response to ocular antigens. Moreover, it is important to determine whether other immune-privileged organs/sites, such as the CNS, are similarly endowed with large numbers of MHC class II-negative DC and to determine the contribution of these cells to tolerance.


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ACKNOWLEDGEMENTS
 
The authors acknowledge the contribution of Mr. Peter Mallen for graphic services.


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FOOTNOTES
 
Current address of Pedram Hamrah: Department of Ophthalmology and Visual Sciences, The Kentucky Lions Eye Center, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY 40202.

Received November 11, 2002; revised February 20, 2003; accepted March 24, 2003.


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