Published: 18 January 2010
`© 2010 Faculty of 1000 Ltd
`
`Ocular immune privilege
`Ru Zhou and Rachel R Caspi*
`
`Address: Laboratory of Immunology, National Eye Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
`
`* Corresponding author: Rachel R Caspi (rcaspi@helix.nih.gov)
`
`F1000 Biology Reports 2010, 2:3 (doi:10.3410/B2-3)
`
`The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/biology/content/2/3
`
`Abstract
`immune and inflammatory responses to preserve vision. This
`The eye attempts to limit local
`phenomenon, known as ocular immune privilege, is mediated by a combination of local and systemic
`mechanisms. While immune privilege is believed to protect the eye from day-to-day inflammatory
`insults, it is not absolute and its mechanisms are still incompletely understood.
`
`Introduction and context
`The eye has a special relationship with the immune system,
`known as immune privilege. The term was coined in the
`1940s by Sir Peter Medawar, who noticed that foreign tissue
`grafts placed in the anterior chamber (AC) of the eye were
`not rejected [1]. While the concept of immune privilege is
`simple, research into its nature has revealed its highly
`complex character, which is still incompletely understood
`(reviewed in [2]). Multiple mechanisms combine to
`maintain immune privilege:
`
`culture) by secreting soluble factors and by contact-
`dependent mechanisms. Retinal glial Müller cells were the
`first to be identified, but their inhibitory surface molecules
`were not characterized [3]. The pigmented epithelia of
`the retina (RPE) and the iris/ciliary body (IPE) not only
`inhibit T cells, but also induce them to become T regulatory
`(Treg) cells [4]. Surface-bound molecules involved in
`these processes include CD86 [which engages cytotoxic T
`lymphocyte antigen 4 (CTLA-4) on T cells], FasL, thrombo-
`spondin, and galectins [4,5].
`
`(a) Physical barriers (efficient blood-retina barrier and
`lack of efferent lymphatics) prevent free entry and exit of
`cells, and even larger molecules, into and out of the eye.
`The integrity of the blood-retinal barrier is routinely
`measured in the clinic by the fluorescein test and provides
`a widely accepted measure of ocular health. Nevertheless,
`the concept of sequestration of the eye from the immune
`system has recently been debated, mostly on the basis of
`the phenomenon known as anterior chamber-associated
`immune deviation (ACAID). (See item (c) below).
`
`(b) The inhibitory ocular microenvironment, composed of
`cell-bound and soluble immunosuppressive factors within
`the eye, inhibits the activity of immune-competent cells.
`The soluble factors include transforming growth factor-beta
`(TGF-b) (which can also be membrane-bound), neuro-
`peptides such as alpha-melanocyte-stimulating hormone
`(a-MSH), vasoactive intestinal peptide, and others. Ocular
`resident cells directly inhibit immune cells (at least in
`
`(c) Finally, the eye actively regulates systemic immune
`responses. The classic example is ACAID, a unique and
`highly orchestrated immune response to antigens injected
`into the AC. It involves migration from the eye to the spleen
`of F4/80+ antigen-presenting cells that interact with
`invariant natural killer T cells and B cells and culminates
`in elicitation of systemic regulatory immunity through
`induction of CD4+ afferent and CD8+ efferent Treg cells
`(reviewed in [4,6]). Proteins and even cells or cellular
`fragments were shown to pass from the AC directly into the
`blood through a highly porous structure known as the
`trabecular meshwork. While some regard this as negating
`the concept of ocular antigen sequestration, elicitation of
`ACAID requires puncturing of the eye with a needle and
`perturbation of ocular integrity. It is therefore likely that
`ACAID is more representative of a response to trauma rather
`than of a mechanism of tolerance to tissue-specific antigens
`contained in the healthy eye. A less controversial example is
`post-recovery tolerance, in which spleen cells from mice
`
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`F1000 Biology Reports 2010, 2:3
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`http://F1000.com/Reports/B/2/3
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`that have recovered from experimental autoimmune uveitis
`(EAU) contain regulatory activity, whose generation is
`dependent on the presence of eye [7-9]. This type of
`tolerance was shown to involve the melanocortin pathway
`and cannot be induced in melanocortin-5 receptor knock-
`out mouse, but whether it is a-MSH from the eye that is
`involved has not been determined.
`
`A highly successful application of the ocular immune
`privilege is corneal transplantation. Corneal allografts
`are up to 90% successful without tissue matching and
`without systemic immunosuppressive therapy [10]. On
`the downside, however, ocular immune privilege may
`leave the eye vulnerable to autoimmunity by impeding
`peripheral tolerance to eye-specific antigens sequestered
`behind the blood-retinal barrier [8].
`
`Major recent advances
`While some effects of neuropeptides that help maintain
`the immunoinhibitory ocular microenvironment may
`be exerted directly on lymphoid cells [5], neuropeptides
`may also regulate production of TGF-b within the eye.
`A recent study demonstrated that immune privilege of
`the eye, as evaluated by rejection of allogeneic tumor
`cells, development of ACAID, and maintenance of high
`TGF-b levels in aqueous humor, was lost following
`removal of functional sympathetic fibers [11]. Thus,
`although some neuropeptides in ocular fluids might be
`produced by ocular cells themselves, sympathetic inner-
`vation of the eye is critical for maintenance of the above-
`mentioned manifestations of immune privilege. This
`could stem from the observed effects on TGF-b as there is
`no evidence from previous studies for direct effects of
`neuropeptides on ACAID and related phenomena.
`
`Recent studies addressing local regulation by pigmented
`ocular epithelia identified previously unrecognized mole-
`cular pathways by which they mediate T-cell suppression
`and their conversion to Treg cells. Ligands for the T-cell
`inhibitory receptor programmed death-1 (PD-1) were
`detected on human as well as mouse RPE cells. Both the
`human ARPE-19 line and primary human RPE express both
`PD-L1 and PD-L2, and expression on primary human RPE
`was enhanced by interferon-gamma (IFN-g). In murine
`RPE, PD-L1 was below detection in primary cells but was
`induced by IFN-g. PD-L1 expression was functionally
`relevant and negatively regulated cytokine production by
`T cells. This could be reversed by blocking antibodies
`to PD-L1 or by PD-1 deficiency [12,13]. RPE cells also
`were found to constitutively produce CTLA-2a,
`a cathepsin L (CathL) inhibitor. CD4+ T cells exposed to
`CTLA-2a-expressing RPE cells or to recombinant CTLA-2a
`converted to CD25+FoxP3+ Treg cells. Importantly, this
`pathway was functional also in vivo and provided protection
`
`from autoimmune uveitis in the mouse EAU model,
`as demonstrated using anti-CTLA-2a antibodies and
`CTLA-2a-deficient mice. CTLA-2a directly lowers CathL
`activity in T cells and also promotes activation of TGF-b by
`facilitating Treg conversion [14,15]. Thus, PD-1 pathway
`may function in suppression of the Th1 responses and
`CTLA-2a may additionally convert T cells that ‘slipped
`through’ the PD-1 pathway into Treg cells. In contrast, the
`T cell inhibitory activity of human IPE was shown to be
`driven by a contact-mediated TGF-b-dependent mechan-
`ism that could be reversed by TGFb2-siRNA (short
`interfering RNA) or anti-TGF-b antibodies [16].
`
`Future directions
`The elaborate and highly redundant nature of mechan-
`isms comprising ocular immune privilege seems undis-
`puted. If things are so good, then why are they so bad? It
`seems unreasonable that in the face of immune privilege
`and in the absence of physical trauma, the eye remains
`vulnerable to autoimmune uveitis in both its clinical and
`experimental forms. As amply demonstrated by experi-
`mental models of induced uveitis, privilege is easily
`broken by even small numbers of activated T-effector
`cells that have been primed in the periphery or
`adoptively transferred [8]. Why are they not inactivated
`or converted to Treg cells by the ocular microenviron-
`ment but allowed to induce destructive inflammation?
`Furthermore, spontaneous uveitis develops when there is
`increased frequency of retina-specific T cells, such as in
`mice lacking the transcription factor AIRE (AutoImmune
`REgulator) which do not delete retina-specific cells in the
`thymus or in mice expressing a foreign protein in the
`retina and having T cells that carry the specific T-cell
`receptor [17,18]. If retinal antigens are indeed seques-
`tered, where are the T cells being primed? And if they are
`not sequestered, why has privilege not resulted in
`systemic tolerance? It would seem that the concept of
`immune privilege needs to be further studied, refined,
`and perhaps revised.
`
`Abbreviations
`a-MSH, alpha-melanocyte-stimulating hormone; AC,
`anterior chamber; ACAID, anterior chamber-associated
`immune deviation; CathL, cathepsin L; CTLA, cytotoxic T
`lymphocyte antigen; EAU, experimental autoimmune
`IFN-g,
`uveitis;
`interferon-gamma;
`IPE,
`iris pigment
`epithelium; PD-1, programmed death-1; RPE, retina
`pigment epithelium; TGF-b, transforming growth factor-
`beta; Treg, T regulatory.
`
`Competing interests
`The authors declare that
`interests.
`
`they have no competing
`
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`http://F1000.com/Reports/B/2/3
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`F1000 Factor 6.6 Must Read
`Evaluated by Matthias von Herrath 07 Dec 2006, Bruno Kyewski
`08 Dec 2006, Arthur Hurwitz 14 Feb 2007
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