Review
International Aichnes of
Allergy™, Immunolog}
Int Arch Allergy Immunol 2005;137:73-81 DOI: 10.1159/000085107
Published online: April 12, 2005
Epithelial Defence by 78 T Cells
Dieter Kabelitz3   Lothar Manschen3   Hans-Heinrich Oberg3 Wolfgang Holtmeierb   Daniela Wesch3
institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, and bMedizinische Klinik I, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
Key Words
Antimicrobial peptides • Chemokine receptors • Cytokines • 78 T cells • Intraepithelial lymphocytes
Abstract
78T cells constitute a separate lineage of T lymphocytes which differ from conventional aß T cells with regard to T cell receptor (TCR) repertoire and tissue localization. In murine skin, 78 T cells expressing a canonical V75 TCR are abundant and contribute as so-called dendritic epidermal T cells to local immune surveillance. In humans, major subsets of 78 T cells are recognized on the basis of their TCR V8 usage. While V82 cells dominate in the peripheral blood, V81 cells are preferentially localized in mucosal tissue including the intestinal epithelia. In this article we summarize basic features of intraepithelial 78 T cells and discuss their possible role in epithelial defence.
Copyright © 2005 S. Karger AG, Basel
Basic Features of 7ft T Cells
In contrast to aß T cells, 78 T cells do not recognize antigen in the context of classical major histocompatibility complex (MHC) molecules, in line with the absence of CD4 or CD8 coreceptors on most 78 T cells. 78 T cells also differ from aß T cells with regard to the germ-line-encoded T cell receptor (TCR) repertoire [1]. While large numbers of variable a and ß genes are available for selection
during intrathymic T cell development, there are only six expressed human V7 genes and a similarly small number of V8 genes [2]. Nevertheless, the 78 TCR repertoire can be at least as diverse as the aß TCR repertoire, due to the tremendous impact of mechanisms such as N nucleotide insertions during TCR gene rearrangement and usage of all three reading frames in the case of D8 elements [3]. Interestingly, however, the expressed 78 TCR repertoire is highly biased, resulting in a preferential expression of some V7/V8 genes in certain anatomical localizations. Thus, in the peripheral blood of adult humans there is a clear preponderance of 78 T cells expressing V79 paired with V82, which can represent 50-95% of all circulating 78 T cells ([4]; the nomenclature of the human V7/V8 genes follows the nomenclature of Porcelli et al. [5]). While V79/V82 cells do not dominate early after birth, the shaping of the peripheral blood 78 TCR repertoire takes place during childhood when the relative expansion of V79/V82 T cells is thought to occur in response to exposure to environmental 78 T cell-stimulating microbial antigens [6]. In most healthy adults, other 78 T cell subsets are present only in low frequency in the blood. The second most frequent subset expresses the V81 element which can be paired with any of the available V7 chains. While V81 cells are a minor population in the peripheral blood, they predominate at mucosal surfaces and are located within the epithelial layer of the small and large intestine [7, 8]. Interestingly, the TCR repertoire of intestinal V81 T cells is highly restricted, as has been shown by sequencing of rearranged junctional regions of V81 transcripts [9, 10]. Similarly to the situation with the V79/V82 T cells in the
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Correspondence to: Dr. Dieter Kabelitz
Institute of Immunology
UKSH Campus Kiel, Michaelisstrasse 5
DE-24105 Kiel (Germany)
Tel. +49 431 5973340, Fax +49 431 5973335, E-Mail kabelitz@immunologie.uni-kiel.de
peripheral blood, the V81 T cells in the intestine are polyclonal at birth and display increasing junctional restriction with age [11]. Importantly, it was found that the V81 TCR repertoires of circulating and intestinal V81 T cells were clearly different in the same individual, suggesting that intraepithelial V81 T cells fulfil functions linked to the recognition of locally displayed ligands or antigens [10]. Alterations in the peripheral blood V81 TCR repertoire occur in certain conditions, notably in the context of viral infections. As an example, characteristic changes in the 78 TCR repertoire are observed in HIV-1 infection with a decrease in V"/9/V82 T cells being associated with a marked expansion of V81 T cells [12-14]. It has been proposed that the expansion of peripheral blood V81 78 T cells in HIV-1-infected individuals might result from the recognition of ligands displayed on the polyclonally activated B lymphocytes [15]. An increase in circulating V81 T cells was also found in renal allograft recipients developing a cytomegalovirus infection. Interestingly, substantial evidence indicated that the expanded V81 T cells responded directly to viral glycoproteins in the absence of antigen-presenting cells [16].
Similar to the above-discussed compartimentalization of human 78 T cell subsets, there is also a strong correlation of the locally expressed 78 TCR repertoire and anatomical localization in the mouse. In contrast to humans, the mouse epidermis harbours large numbers of 78 T cells, commonly known as dendritic epidermal T cells (DETC) [17]. The 78 DETC appear to be of thymic origin and express a canonical V75 TCR (nomenclature of Heilig and Tonegawa [18]), suggesting that they recognize an antigen restricted to the epidermis [19,20]. At least some 78 T cells, notably intestinal intraepithelial lymphocytes (IEL) expressing V77, are generated in the absence of a functional thymus [21]. A very recent study has extended these findings to demonstrate that 78 IEL can develop in athymic nu/nu mice lacking all lymph nodes including mesenteric lymph nodes, Peyer's patches, and the recently identified intestinal isolated lymphoid follicles [22], suggesting that at least some lymphoid cells can undergo TCR gene rearrangement in the gut mucosa.
Migration of 7ft T Cells to Intestinal Mucosa and Skin
At least two mutually non-exclusive pathways orchestrate the ordered migration of lymphocyte subsets to defined target tissues, i.e. the interaction between adhesion molecules with their corresponding receptors, and the
chemoattraction by locally produced chemokines of lymphocytes selectively expressing the adequate chemokine receptor [23]. Intestinal homing T lymphocytes express the chemokine receptor CCR9 and migrate in response to the chemokine CCL25/TECK which is produced in the small intestine [24]; as a consequence, CCR9 knockout mice have a severe deficiency in intraepithelial 78 T cells [25]. CCR9 is also expressed on intestinal homing human T cells and other mucosal lymphocytes [26]. While the expression of CCR9 on human 78 as compared to aß T cells has not been analyzed before, we have recently investigated this issue on peripheral blood and intestinal IEL 78 T cells. We found very low expression of CCR9 on V81 and V82 blood 78 T cell subsets ex vivo and substantially higher induction on V81 as compared to V82 T cells upon TCR-dependent cellular activation. Furthermore, IEL 78 T cells strongly expressed CCR9 (as did aß IEL) and maintained high level expression upon extended in vitro culture, in striking contrast to the aß IEL. Thus, it appears that CCR9 also plays a crucial role for the intestinal localization of human 78 T cells.
The migration of T cells to the skin is governed by other chemokines, notably CCL17 (TARC) and CCL27 (CTACK) and their respective receptors CCR4 and CCR10 [27-29]. CCR4, however, is not selective for skin-homing lymphocytes but also governs migration of lymph node homing T cells in response to CCL22/MDC. In human peripheral blood lymphocytes, CCR4 is induced on V82 78 T cells upon TCR-dependent stimulation by bacterial phosphoantigens [30], and we also observed a strong CCR4 expression on IEL-derived human 78 T cell lines. Taken together, it appears that similarly to conventional aß T cells, the coordinated expression of a selected set of chemokine receptors is correlated with the tissue localization of 78 T cells [ 31 ]. In addition to chemokines and their receptors, integrins are critically involved in this process. The integrin aEß7 (CD 103) is expressed by IEL and mediates lymphocyte adhesion to epithelial cells by interacting with the specific ligand E-cadherin [32]. Interestingly, the expression and the function of aEß7 integrin is regulated by the chemokine CCL25, giving rise to a functionally important cross-talk with CCR9 on mucosa-seeking T cells [33].
Antigens Recognized by 7ft T Cells
Conventional aß T cells recognize processed peptides in the context of MHC class I (CD8+ T cells) or MHC class II molecules (CD4+ T cells). Instead, most 78 T cells
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recognize different ligands, and usually in an MHC-non-restricted fashion [for reviews, see 1, 31]. The dominant subset of 78 T cells in human peripheral blood expressing V79 paired with V82 recognizes small microbial pyrophosphates derived from the bacterial non-mevalonate pathway of isoprenoid biosynthesis ('phosphoantigens') [34, 35]. Such phosphoantigens are produced by a variety of pathogenic bacteria, and rapidly induce proinflammatory cytokines including tumour necrosis factor-a and interferon-"/ in V79V82 T cells [36, 37]. Human 78 T cells expressing V81 are preferentially found among IEL as compared to peripheral blood. The V81-encoded TCR recognizes MHC class I-related molecules (MICA/MICB) that are induced on epithelial cells by stress, suggesting that V81 78 T cells contribute to local immune surveillance [38-40]. Importantly, the stress-induced MICA antigens as well as some distantly related ULBP proteins are also ligands for NKG2D, an activating NK receptor expressed on 78 T cells, NK cells and some aß T cells [41,42]. Therefore, such MHC class I-related molecules which are induced on damaged ('stressed') epithelial cells can alert 78 IEL (notably V81 cells) via multiple cell surface receptors. In addition, human V81 78 T cells have been found to recognize CD 1 antigens [43] and cytomegalovirus proteins in the absence of MHC-dependent presentation [16].
In contrast to human V79V82 T cells, murine 78 T cells do not recognize bacterial phosphoantigens, due to a lack of homology in critically important TCR sequence residues. Therefore, it is impossible to use simple mouse models to address the pathophysiological significance of 78 T cell-mediated phosphoantigen recognition in vivo. Instead, murine 78 T cells have been found to recognize mycobacterial heat shock proteins, inducible MHC class lb molecules T10/T22, poorly defined ligands on stressed keratinocytes and stressed intestinal epithelial cells [44-47], as well as a range of additional ligands [1, 31].
Effector Functions of 7ft T Cells
The effector functions of activated 78 T cells resemble in many aspects those of conventional aß T cells. Thus, 78 T cells produce cytokines and frequently exert potent cytotoxic effector function involving both perforin/gran-zyme and Fas/Fas ligand-dependent pathways [48, 49]. Although most 78 T cells seem to be primed towards the production of Thl-type cytokines, they have the intrinsic capacity to make Th2 cytokines including IL-4 if activated under appropriate Th2-driving conditions [50, 51]. However, a few seemingly specific effector functions of 78
T cells have been described. A striking example is the production of keratinocyte growth factor (KGF) by murine 78 DETC and 78 IEL [52]. Human 78 but not aß T cells produce connective tissue growth factor (CTGF) which regulates wound healing and fibrinogenesis [53]. Moreover, human 78 T cells also produce fibroblast growth fac-tor-9 (FGF-9) as well as KGF [54]. These observations are well in line with the notion that 78 T cells play an important role in epithelial repair mechanisms. In addition, several groups have searched for 78 T cell- and possibly localization-specific gene expression using transcriptional profiling and serial analysis of gene expression in murine 78 T cells [55-57]. These studies identified a variety of genes that are preferentially expressed by 78 IEL, and also revealed the rather unexpected overexpression of genes involved in lipid metabolism and cholesterol homeostasis [55].
Principles of Antimicrobial Epithelial Defence
In recent years it has emerged that naturally occurring antimicrobial peptides (AMP) play a central role in innate immune defence. Such AMP are produced by epithelial cells in the intestine, skin and elsewhere. Major classes of AMP comprise the defensins, the cathelicidins, and other peptide families including some RNases and members of the S100 protein family such as psoriasin [58-61 ]. Defensins are small polypeptides which exert their antimicrobial activity by permeabilization of the outer and inner bacterial cell membrane [62]. There are two major subfamilies, i.e. a- and ß-defensins which share certain structural features but differ in other aspects. In humans, a-defensins are constitutively expressed and stored in granules in neutrophils, Paneth cells of the small intestine, and epithelial cells. In contrast, the expression of ß-defensins in epithelial cells and the epidermis requires stimulation, e.g. by bacteria or bacterial products [58]. Some AMP require processing to exert bactericidal activity. Thus, the precursor of a-defensin is cleaved in murine Paneth cells in the small intestine by the matrix metalloprotease-7 (MMP-7 or matrilysin) [63-65]. The processing of the human cathelicidin hCAP-18 is mediated by a different protease, the serine protease proteinase 3. The cleavage of the C-terminal part by proteinase 3 liberates the antibacterial and cytotoxic peptide LL-37 [66]. LL-37 is a multifunctional molecule which, in addition to its bactericidal activity, exerts multiple modulatory effects on innate immune responses. In particular, LL-37 modulates gene expression in monocytes, induces IL-Iß processing
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and release, and influences the differentiation of dendritic cells and dendritic cell-induced T helper cell polarization [67-69]. At the molecular level, at least some of these effects are linked to the activation of mitogen-activated protein kinases ERK1/2 and p38 [70, 71]. Remarkably, the production of cathelicidin/LL-37 is not restricted to epithelial cells and keratinocytes but is also observed in neutrophils, monocytes and mast cells [72-74]. Most interestingly, LL-37 expression at the mRNA and protein level was also found in human 78 T cells [73], well in line with our own observations. This raises the possibility that 78IEL could directly contribute to antimicrobial defence by producing certain AMP (see below).
Defensins are not typically produced by immune cells, a-defensins HNP1-3, however, are expressed by some NK and T cells [73], and are induced in NK cells upon stimulation with bacterial products such as flagellin [75]. In addition, Duits et al. [76] observed expression of ß-defensin-1 (hBD-1) and hBD-2 in human blood monocytes and alveolar macrophages, supporting the idea that monocyte and/or dendritic cell-derived ß-defensins might contribute to orchestrating an immune response by attracting T lymphocytes via the ß-defensin receptor CCR6 [76, 77]. In this regard, it is of interest that we recently observed the strong expression of CCR6 on IEL-derived but not on peripheral blood-derived 78 T cell lines, suggesting a structural basis for a cross-talk between epithelial cells and 78 IEL. In addition, we also found expression of hBD-2 mRNA by RT-PCR in a proportion of the analyzed human 78 T cell lines. A systematic analysis of de-fensin expression in IEL-derived 78 T cells is under way in our laboratory.
Regulatory Role of 7ft T Cells in the Skin
As mentioned above, the mouse skin harbours large numbers of 78 DETC. These DETC express a canonical V75V8I TCR with identical junctional sequences and are activated by coculture with stressed keratinocytes. The activation of DETC by stressed keratinocytes requires cell-cell contact, suggesting TCR-mediated recognition of self antigen [46]. In their recent experiments, Jameson et al. [78] isolated low molecular weight fractions from stressed murine keratinocytes which activated 78 DETC but not 78 T cells from other tissues expressing different TCR. Further work is needed, however, to precisely identify the antigen seen by the DETC TCR. In any case, it appears that the 78 DETC present in murine skin play a non-redundant role in the local surveillance of stressed or
damaged keratinocytes. TCR8_/~ mice lacking all 78 T cells still have some DETC which express a polyclonal aß TCR instead of the canonical 78 TCR. Interestingly, these aß DETC can be activated by mitogen or anti-CD3 antibodies but do not respond to keratinocyte damage, indicating the unique role of the 78 TCR expressed on DETC [79]. The close contact of epidermal keratinocytes with 78 DETC suggests a critical function of the DETC in the process of wound healing. In fact, it has been found that 78 DETC produce KGF-l/FGF-7 in response to contact with damaged keratinocytes, which supports keratinocyte proliferation and thus wound repair [80]. As shown in a skin organ culture system, keratinocytes proliferated at the wound site of wild-type skin but not skin from TCR8-7- mice. In addition to KGF-l/FGF-7, FGF-10 was also expressed in 78 DETC and thus could also contribute to early keratinocyte proliferation [81]. Taken together, these results indicate that 78 T cells play an important role in the process of wound repair in the mouse skin by producing KGF. In addition, 78 T cells also regulate local cutaneous inflammatory reactions. This was nicely shown in a study by Giradi et al. [82] where the authors investigated spontaneous dermatitis occurring in TCR8_/" mice of different genetic backgrounds. While both NOD.8_/" and FVB.8_/" mice spontaneously developed localized chronic dermatitis, C57BL/6.8"7" mice did not. The dermatitis was associated with the accumulation of large numbers of aß T cells in the skin, suggesting that 78 DETC are important in controlling migration of inflammatory aß T cells into the skin. Other reports have shown that local 78 T cells also regulate contact hypersensitivity. TCR8_/" mice showed increased contact hypersensitivity responses, due to uncontrolled activity of hap-ten-specific CD8+ T cells [83]. Together with many additional studies not cited here for lack of space, these results underline the idea that 78 T cells have important immunoregulatory functions, especially when located in epithelial and mucosal tissue [84].
78 T cells also contribute to the control of cutaneous malignancy in mice. As shown by Girardi et al. [85], mice lacking 78 T cells were much more susceptible to developing cutaneous malignancy in a two-stage tumour initiation and promotion model. After exposure to carcinogen, the skin cells expressed MHC class I-related molecules, Rae-1 and H60 molecules, which are ligands for NKGD2 receptors on local 78 T cells in wild-type mice. In this model of chemically induced skin cancer development, 78 T cells are strongly protective, while aß T cells can contribute to tumour progression [86]. Together, this is clear evidence that local 78 T cells fulfil an important
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Fig. 1. Possible functions of intraepithelial 78 T cells. The DETC in the mouse skin are 78 T cells expressing a canonical T cell receptor (V"y5). Although intraepithelial 78 T cells in the gut mucosa are somewhat more diverse, they preferentially express V"/7 in the mouse and V81 in humans. Intraepithelial 78 T cells can be activated via two pathways: (1) TCR-dependent ligand recognition and (2) binding of stress-induced MHC class I-related molecules on epithelial cells (MICA/B, ULBP in humans, Rae-1/H60 in the mouse) to activating NKG2D receptors expressed on the 78 T cells. Possible effector functions of the activated 78 T cells are listed in the boxes on the left hand side.
. Production of repair cytokines: -KGF - FGF-9 -CTGF
2. Killing of damaged cells:
- perforin/granzyme B
- Fas/Fas-Ligand
3. Production of AMP/ antimicrobial activity:
- cathelicidin/LL37
- granulysin
- others (hBD-2) ?
4. Crosstalk with epithelial cells:
- via ß-defensin receptor CCR-6
- production of AMP-processing metalloproteases (MMP-7)?
5. Regulation of immune responses: -IL-4 -TGF-ß - chemokines
role in downregulating epithelial malignancy. Other potential functions of 78 DETC, such as the possible production of AMP, have not yet been investigated.
Function of 7ft T Cells in the Intestinal Mucosa
78 T cells constitute a major proportion of the IEL population in the intestinal mucosa. It appears that IEL 78 T cells also exert a non-redundant function in the mucosal tissue. Chen et al. [87] used the dextran sodium sulphate (DSS)-induced mouse colitis model to address this issue. They noted an accumulation of large numbers of 78 but not of aß T cells at the sites of DSS-induced epithelial cell damage. More severe colitis and delayed tissue repair were observed in TCR8_/~ mice lacking all 78 T cells. Again, KGF was identified as the 78 IEL-derived growth factor that promoted localized epithelial cell proliferation and thus tissue repair following DSS-induced colitis. Very similar results were obtained by Yang et al. [52] in a different in vivo model, i.e. villus atrophy induced by total parenteral nutrition and villous hypertrophy resulting from a short bowel syndrome. The former was associated with a downregulation of 78 IEL-derived
KGF, whereas upregulation was observed in the latter case. This is additional evidence that IEL 78 T cells critically control epithelial cell growth through the production of appropriate growth factors. Moreover, a recent study points to an important role of the transcription factor interferon regulatory factor-1 (IRF-1) in the control of intestinal 78 T cell homeostasis. As shown by Sieg-mund et al. [88], IRF-1 knockout mice developed a dramatically more severe colitis and showed higher mortality than wild-type mice following DSS treatment. Interestingly, the IRF-1~'~ mice had much fewer 78 IEL (<50°/o) as compared to wild-type mice. While the reduced number of 78 IEL might contribute to the development of colitis in the IRF-1 _/~ mice, it is clear that other mechanisms are also involved, such as the strongly reduced production of the IL-18 antagonizing IL-18 binding protein in these mice [88].
On the basis of their distribution and cluster formation with epithelial cells, it is likely that 78 IEL also play a role in the local surveillance of the human gut epithelium [89]. The function of intestinal 78 T cells in inflammatory bowel disease in humans is not completely understood. Reports on increased numbers of 78 T cells in the inflamed mucosa [90] contrast with contradictory studies [see 8,
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91]. Several reports indicate an accumulation and clonal expansion of 78 T cells in the inflamed mucosa of patients with Crohn's disease [92,93] as well as increased numbers of V81 78 T cells also in the peripheral blood [91, 94]. However, the molecular analysis of the TCR8 repertoire revealed a lack of dominant clones in the inflamed mucosa, but distinct repertoires in the intestine as compared to blood [8, 95]. Human 78 IEL frequently express V81 which recognizes the stress-inducible MICA antigens. This allows V81 78 T cells to control epithelial integrity by eliminating stressed or damaged cells, similarly to the above-described situation in the mouse skin. In addition to 78 T cells, other lymphocyte populations including the NKT cells expressing invariant Va24Vß 11 TCR are likely to contribute to intestinal immunity and epithelial defence [96]. Presently, it is not known whether 78 IEL contribute to antimicrobial defence by producing AMP. Our preliminary results would indicate that some 78 T cells express certain AMP. In addition, we found that 78 T cells can express matrilysin (MMP-7), suggesting that 78 T cells might contribute to epithelial homeostasis via production of this metalloprotease known to be required for a-defensin processing in Paneth cells of the mouse gut [63, 64].
Concluding Remarks
Local 78 T cells can be activated by diverse stimuli such as stress-induced self antigens expressed on epithelial cells/keratinocytes due to infection, DNA damage, or carcinogen contact. As summarized in figure 1, these 78 T cells can among other things (1) assist wound healing by providing keratinocyte and fibroblast growth factors, (2) kill unwanted damaged cells via perforin/granzyme and/or Fas-Fas ligand-dependent pathways, (3) potentially mediate direct antimicrobial activity by producing certain AMP, (4) possibly communicate with epithelial cells via CCR6, and (5) exert immunoregulatory activity through the release of cytokines and chemokines [83, 84, 97-100]. Therefore, 78 IEL located in the skin or in the intestinal mucosa constitute an integral part of epithelial defence mechanisms.
Acknowledgements
Our work cited in this paper was supported by the Deutsche Forschungsgemeinschaft (SFB 617 project A16). This work forms part of the PhD thesis of Lothar Marischen.
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