Eur Respir J 1993, 6, 120-129 REVIEW

Regulation of antigen-presenting cell function(s) in lung and airway tissues

P.G. Holt

Regulation of antigen-presenting cell function(s) in lung and airway tissues. Correspondence: P.G. Holt P.G. Holt. Division of Cell Biology ABSTRACT: A variety of cell populations present in respiratory tract tissues The Western Australian Research can express the function-associated molecules on their surface which are re­ Institute for Child Health quired for presentation of antigen to T-lymphocyte receptors. However, the GPO Box 0184 Perth, Western Australia 6001. potential role of individual cell populations in regulation of local T -lymphocyte· dependent immune reactions in the lung and airways depends on a variety of Keywords: Antigen presentation additional factors, including their precise localisation, migration characteris­ airway epithelium tics, expression ofT-cell "eo-stimulatory" signals, responsiveness to inflamma­ class li MHC (I a) antigen expression tory (in particular cytokine) stimuli, host immune status, and the nature of the T-lymphocyte activation antigen challenge. Recent evidence (reviewed below) suggests that tJ1e induc­ tion of primary immunity (viz. "sensitisation") to inhaled antigens is normally Received: April 30, 1992 controlled by specialised populations of Dendritic Cells, which perform a sur­ Accepted: September 8, 1992 veillance role within the epithelia of the upper and lower respiratory tract; in the pre-sensitised host, a variety of other cell populations (both bone-marrow derived and mesenchymal) may participate in re-stimulation of "memory" T­ lymphocytes. Eur Respir J .. 1993, 6, 120-129.

Aberrant immunoinflammatory responses to exog­ control of T-cell activation is normally operative to enous antigens are important aetiological factors in a protect the lung against unnecessary and/or exagger­ large proportion of the common non-malignant respi­ ated responses to foreign antigens. ratory diseases. The inflammatory processes which produce the characteristic pathology in these diseases, are controlled directly or indirectly by the secreted Identification of APCs in respiratory tract tissues products ofT-cells, and result ultimately from a chain in situ: immunostaining of cells expressing class ll of cellular reactions initiated by the "presentation" of major histocompatibility complex (MHC) inhaled foreign antigen to the T-cell receptor. This immune region associated (la) antigen presentation event may occur locally, giving rise to im­ mediate activation of cytokine producing memory T­ Surface expression of Ia is a necessary prerequisite cells in the airway mucosa [1], and lumen [2), as has for "presentation" of antigen to the T-cell receptor, been observed in chronic asthmatics, or systemically, and, in general terms, the concentration of la on the particularly in the regional lymph nodes draining the cell surface correlates with the potency of APCs in respiratory tract, where initial "priming" of the naive T-cell activation l4J. Thus, potential APCs may be immune system occurs following inhalation of antigens identified in tissue sections by immunoenzymatic stain­ not previously encountered [3). ing employing monoclonal antibodies against la. The immunological sequelae of these initial T -cell A substantial literature is available from studies which activation events are highly variable and can range have applied this technology to lung tissue. from T-cell anergy or tolerance, to the manifestations Cells expressing la are abundant in lung tissues of of hypersensitivity and associated tissue pathology. all speci.es examined, and are found both within epi­ The eventual outcome of individual encounters with thelial and submucosal sites throughout the conduct­ inhaled antigens depends to a significant extent on the ing airways, and within the connective tissues functional capacity of the antigen-presenting cells sur- rounding blood vessels and alveolar septal walls (APCs), which initially sequester the antigens. Recent in the lung parenchyma. The precise identity of information on the nature of APC populations in dif­ immuno-stained cells in lung tissue sections has been ferent tissue microenvironments in the respiratory tract, understandably controversial, in view of the difficul­ reviewed below, suggests that a high level of local ties associated with controlling the plane of section; REGULATION OF APC FUNCTION IN AIRWAYS 121

particularly with small biopsy samples from human co-stimulator(s) by DCs is constitutive [8, 9), whereas lung. Interpretation of the human literature is further­ macrophages and B-cells produce Httle, unless they are complicated by the paucity of data on normal control pre-stimulated with natural "adjuvants", in particular tissue. bacterial cell wall antigens conttlining lipopolysaccha­ At least seven major cell types have been positively ride [8]. Mesenchymal cells, such as epithelia and identified as expressing la in healthy or diseased lungs: fibroblasts, are believed to be generally incapable of B-lymphocytes, activated T-lymphocytes, fibroblasts, delivering an effective co-stimul.ator signal [ 10], dendritic cells (DCs), and macrophages - the latter although this issue is controversial. can be further subdivided (only in humans) into resi­ Host immune status is also an important determinant dent pulmonary alveolar macrophages (PAMs), infil­ in selecdon of appropriate APCs. It is now recognized trating monocytes present in either extraceilular fluids that naive (i.e. non-immune) and memory-T-cells have on the alveolar surface or within solid ti ssues, and ma­ different requirements for anligen-specific activation. ture tissue macrophages. With the exception of la+T­ In particular, with respect to soluble protein antigens, Iymphoblasts, all of Lllese latter cells have been monocytes/macrophages and B-cells funcrion very invoked as potential regulators of antigen specific T­ poorly in presentation of inductive signals to naive T­ cell responses to inhaled antigens, and the salient as­ cells. whereas they effecrively stimulate responses in pects of rhe supporting evidence for these claims is memory T-cells [9, 11 , 12, 13]. DCs appear unique reviewed below. in their capacity to present soluble protein antigens to non-immune T-cells [9J and hence prime/sensitize the naive host. Factors determining the contribution of potential The situation with respect to the induction of pri­ APC populations to individual immune responses mary immunity to particulate antigens is less cle~u·, as in the lung DCs are actively endocytic. but appear non-phagocytic The cell populations detailed above ctul be broadly in vitro L9). However. at the ultrastrucrural level, c lassified as "professional" APCs (B-cells, mature DCs exhibit cytoplasmic inclusions character­ macrophages and DCs) or "opportunistic" APCs (air­ istic of secondary lysozomes, prompting suggestions of wHy epithelial cell s . Type ll pneumocytes and phagocytic activity al an earlier stage of their life fibroblasts). The potential for each cell population to cycle in vivo [14]. participate in an immune induction event in the respi­ Based on the above, our current understanding of the ratory tract is determined by two sets of interacting role of the various candidate APCs is outlined below. factors: hos t· immune status, and the physicochemi­ cal properties of the inhaled antigen. APC populations in normal lung It is axiomatic that large insoluble particulate anti­ gens will gain only limited access to cell populations Dendritic cells below epithelial surfaces, and hence U1e transmission of antigenic signals to the T-cells system from such The presence of DCs in human parenchyma] lung sources requires the participation of actively phagocytic tissue was initially associated with underlying inflam­ cells, which function at the level of L11 e airway matory and fibrotic disease states [15. 16]. However, lumenal suli'ace. Moreover. the relevam APC requires they were subsequently identified as normal residents the additional capacity to migrate selectively to T-cell of the uirway epithelium and alveolar septa in all spe­ zones in regional lymph nodes, in order to induce a cies [17-20]. primary immune response in a naive host. The first evidence of a role for these cells in anti­ In contrast, low molecular weight soluble antigens, gen presentation to T-lymphocytes, was provided by may be expected to be readily translocated to intra­ a study on rat lung from our laboratory [211. These epithelial or submucosal. microenvironments via intrn­ experiments employed collagenase digestion to extract ceUular (pinocytic) or imercellular pathways [5], and mononuclear cells from lung parenchyma) tissue, prior hence gain access to all the potential APC populations to assessment of APC activity in various cell fractions listed above. This class of antigen, typified by Dcr of the digest. The phenotype of Lh e principal APC in p I allergen from the house dust mite. which leaches lhese digests was non-adherent, non-phagocytic, sur­ rapidly into epithelial lining nuids after impaction on face immunoglobulin (slg-), la• and of ultra-low den­ the airway surface [6], appears particularly effective in sity on percoiJ gradients, consistent wilh their identity inducing immunologically-mediated disease. as DCs L21]. These results were confirmed and ex­ A further factor of importance, relates to the capac­ tended to include an identical population in the airway ity of individual antigens to directly "stimulate" aspects epithelium [20J, and similar observations have si nce of APC function. It is now recognized that for ef­ been reported for other species including humans [ 18, fective T-cell activation the APC requires to deliver 22-24]. A consistent finding in these studies has been rwo simultaneous signals to the T-cell-rcceptor, firstly the presence of an endogenous macrophage population processed antigen (peptide) complexed with s urface in lung tissue digests, which inhibits DC-ioduced T­ MHC class 11 (la), and secondly a ''co-stimulator" ceJI activation in vitro L20. 2 1, 25. 261. We have sug­ signal (or signals) supplied vitt a second group of gested that the induction of T-cell immunity in the cell s urface molecules [7]. The production of l ungs is co-ordinately regulated in vivo by 122 P.G. HOLT

countermanding signals from these two cell types [20, to sequester inhaled antigen in situ and to be capable 2L). of processing and subsequently presenting the An important consideration in assessing the poten­ antigen to immune T-cells in vitro, thus establishing tial importance of DC populations in regulation ofT­ their capabilities as potential APCs in vivo. However, cell dependent immunity in the respiratory tract, is their functional capacity does not appear to be static their distribution in vivo, and their contribution to but like cells in the mononuclear phagocyte lineage, overall expression of class II MHC (la) in these alters radically during maturation. Based upon tissues. The general impression from the literature is available data on DC populations from other tissues that expression of la in the deep (peripheral) lung is (reviewed in [9]), it may be assumed that the extremely heterogeneous, e.g. [19], and even in speci­ majority of lung DCs initially arrive via the blood as fied pathogen free (SPF) animals the Ia• population in monocyte-like DC precursors, and home selectively to the alveolar region can include DCs, macrophages, B­ intraepithelial microenvironments. They mature in situ cells and Type li alveolar epithelial cells. However, into Langerhan's-like DCs over a period of weeks, dur­ in a recent study with SPF rats employing dual col­ ing which time they sample, process and "store" in­ our immunostaining of frozen sections with a panel of haled antigens; they eventually migrate from their monoclonal antibodies (MoAbs) specific for surface epithelial environment (possibly under the influence of antigens on DCs and/or macrophages, the DCs were cytokine signals such as tumour necrosis factor ex estimated to comprise up to 25% of the overall Ia+ cell (TNFa) [32], and selectively home to T-cell zones in population resident in the normal lung parenchyma the regional lymph nodes (9]. Analogous to epider­ [27). This figure may be an underestimate, given the mal Langerhan's cells, lung DCs function relatively likelihood that a random plane of section would in poorly as APCs when freshly isolated from lung tis­ many cases reveal only part of the cell body of highly sue, but mature into extremely potent APCs during pleiomorphic DCs. overnight culture in medium containing T-cell-derived Interpretation of immunoperoxidase staining patterns cytokines [27, 33]. This suggests that their primary in tissue samples from the conducting airways has, function in vivo is to serve as a "sentinel" cell in the hitherto, been similarly complex. However, we have respiratory tract at the epithelial interface with the out­ recently developed a novel approach to this problem, side environment, sampling incoming antigens for stimulated by published data on the DC population in eventual presentation to the immune system in the re­ the epidermis (Langerhan's cells) [28]. The highly de­ gional lymph node. Their relative inability to present veloped Langerhan's cell network was only revealed by inhaled antigen to T -cells during the intraepithelial the use of epidermal sheets for immunostaining, which phase of their life cycle may be a protective mecha­ provide an en face view of intraepidermal cells. To nism, limiting T-cell-mediated damage to host epithe­ achieve a comparable plane of section with isolated lial tissues, which would inevitably accompany local airway segments, sequential frozen sections are taken T-cell activation [27]. tangentially parallel to the long axis of the tube, even­ The fact that these DCs constitute the only resident tually yielding fields of view through the epithelium cell population within the normal airway epithelium parallel to the underlying basement membrane. which constitutively expresses la, strongly suggests Immunoperoxidase staining of la in such tangential that they constitute the "first line of defence" against sections reveals a picture which is in marked contrast inhaled antigens. As such, they are likely to play a to the apparently heterogeneous staining pattern seen major role in the aetiology of both allergic and infec­ with conventional transverse sections, demonstrating tious diseases (in particular viral), in the respiratory instead that virtually all la expression in non-inflamed tract [29, 31). airway epithelium of rats [29], and humans [30], can be accounted for by cells with the characteristic mor­ Mononuclear phagocytic cells (MPC) phology of DCs. Detailed morphometric analysis of la staining in the Substantial macrophage populations are present rat airways indicates an inverse relationship between within both the airway lumen [34], and the lung airway diameter and intraepithelial DC density, which interstitium [35, 36J, and these cells are accessible for varies from 500- 600 cells·mm·2 epithelial surface in study, respectively, by bronchoalveolar lavage (BAL) the trachea (equivalent to published figures for the epi­ and collagenase tissue digestion. A third population dermis) down to approximately 50 cells·mm2 in small can be found in the airway wall and, in normal airways below generation 5 [31), suggesting that DC tissue, is restricted to the submucosal side of the epi­ population density relates directly to the intensity of thelial basement membrane [27). inflammatory stimulation provided to the epithelium by Studies on the APC function(s) of these MPC the outside environment [31]. The limited information populations have focused principally on pulmonary available to us on humans [30], suggests that this gra­ alveolar macrophages (PAMs). The literature in this dation is much less marked, possibly indicating differ­ area has been somewhat controversial, as variations ence in life span and hence cumulative inflammatory have been reported in PAM activity in in vitro T-cell stimulation of the smaller airways. culture systems, both between species, and within in­ Both the airway intraepithelial DCs [20] and their dividual species (including human), employing differ­ alveolar septal wall counterparts [27) have been shown ent T-cell activation stimuli. However, employing REGULATION OF APC FUNCTION IN AIRWAYS 123

antigenic (as opposed to polyclonal) stimu lation. large-scale upregulation of APC capacity in sir11, de­ particularly at macrophage:lymphocyte ratios above monstrable within 24 h of treatment !54j. Addition­ I :5, PAMs from human and most animal species are ally, LI:Je in vitro "maturation'' of APC funclions, which actively lymphocytostatic and inhibit T-cell activation normally occurs during overnight culn1re of purified (reviewed in l37]). Interstitial milcrophage populations .lung DCs 1271. can be completely inhibited by are also inhibitory to T-cell activation in 1•itro. albeit eo-incubation with PAMs across a sen1i-permeable less effectively than PAMs l20. 2 1, 38]. membrane [56]. Experiments are in progress The renewal of the resident PAM population in the in our laboratories to identify the cytokines which me­ steady state is 11ia <1 combination of local division diate these effects. of precursors (probably including nn interslitial com­ These findings suggest that clown-motlulation of the ponent) and recruiunent of blood monocytes, the APC activity of DCs may represem a major pathway latter component increasing dnunatically in response to by which resident PAMs regulate the immunological local inOammation [39-431). The resident PAM popu­ milieu of the lung. ll is of interest to note, in this lation. sampled at a static time point, will reflect ac­ contex't, that analysis of the distribution of PAMs on cordingly reflect a continuum of maturation from the surface of surgically removed human lungs, in monocyte to mature PAM. lt is cl.ear that the sup­ which retention of these cell s in siru hall been pressive phenotype of lhe resident PAM is acquire(] optimally preserved by vascular perfusion-fixation, in­ dw·ing this maruratlon process, e.g. f44J, as monocyrcs dicated that all PAMs were closely juxtaposed to al­ from most species function effectively in APC assays. veolar septal functions f56]. Our observations, in rar Consistent with this notion, fractionnti.on of PAM lung immunostaincd for la. indicate that the majority populations. by unit gravity or density gradient sed.i­ of Ja+ DC-Iike cells are located within these same al­ mentation. reveals the presence of subsets which vary veolar septal junctional zones <'.,!( . [57], i.e. separated in activity rrom stimulatory to inhibitory towards from adjacent PAMs by the width of a single Type I T-cell activation [45-49J. The activity of these func­ alveolar epithelial cell. A similar juxtaposition tionally distinct subsets can also be demonstrated by occurs in the airway mucosa, where DCs and mature appropriate dose-response manoeuvres f50j. lt is also tissue mncrophnges arc aligned on opposite sides of relevant to note that small numbers of PAMs are able the epithelial basement membrane [271. ro migrate from the alveoli to regional lymph nodes f5l,l. where they home to T-cell regions L521. lt is not known whether the signals that they proville ro T­ Epithelial cells cells in thar microenvironment arc stimulatory or in­ hibitory. In antigen expression by ostensibly normal ahway However, under steady-state conditions. the net in epithelial cells !58, 591 raises the question of Ll1eir pos­ vitro effect of the overall PAM population is consist­ sible role in regulation of local T-cell responses. ently immunosuppressive l37]. Compelling evidence Several recent studies have presemed evidence that in support of a similar suppressive role for PAMs human bronchial epithelial cells may upregulate T-cell in vivo has recently been provided, from studies activation in l'itro. Firstly. airway epithelial cells involving their selective elimination in situ by the precultured for s ix dnys in nutritionally- limiting intratracheal administration of liposome-encapsulaled medium have been shown to stimulate ~•llogeneic MLR dichloromethylene diphosphonate (DMDP). The reactions [60]. However. the authors were unaware of liposomes are avidly phagocytosed by PAM, leading the magnitude of potential contamination with to the death or the majority of these cells over the intraevirhelial DCs (llnd possible precursors - a ensuing 12- 24 h f53J; minimal translocation of the further unresolved issue) which cou ld comprise up to drug occurs inro the lung or airway wall, and no cel­ I(}' cells·mnr2 epithelium f30, 311; furthermore, aiT­ lular infiltrate is observed !53, 54 1. Subsequent anti­ w:iy epithelia are known sources of cytokines such as gen exposure via intratracheal injection or aerosol granulocyte/macrophagc colony-stimulating factor inhal

The eo-stimulatory activity of the epithelial cells may Inflammation-induced changes in lung reflect their capacity to produce mediators which are APC populations known to modulate the function(s) of DCs and/or macrophages [61, 62, 65]. Type II alveolar epithelial cells have recently also Dendritic cells been recognized to constitutively express la [66]. Analysis of their performance in mitogen-stimulated Recent studies in rats from our laboratory [31] have cultures of splenocytes demonstrated their capacity to demonstrated marked increases in airway intra­ block lymphocyte proliferation, without inhibiting epithelial DC density in acute inflammation induced by activation as measured by interleukin-2 (IL-2) receptor inhalation of bacterial lipopolysaccharide. The kinet­ expression [67]. These effects are reminiscent of the ics of this DC response mimicked that of the neu­ suppression/anergy induced by exposure of specific trophil response, waxing and waning over a 48 h T -cells to antigen-pulsed Ia+ keratinocytes [ 10, 68]. period, thus providing the immune system with an in­ which is believed to result from stimulation of the creased rate of "sampling" of antigens within the tis­ T-cell receptor in the absence of the obligatory sue milieu at the site of inflammation. Additionally, "co-stimulator" or second signal required for T -cell in experiments using an animal model of chronic air­ proliferation. No information is currently available on way inflammation induced by long-term exposure to the activity of these cells in relation to antigen­ pine dust (used as a model for cedar workers asthma), specific T-cell activation. in which the airway epithelium expresses high levels of la and displays marked local eosinophilia, we have Fibroblasts demonstrated that DC density (and la expression) in­ Recent studies on murine lung fibroblasts, indicate the creases to approximately double control levels l31). exjstence of two distinct subpopulations on the basis Parenteral administration of recombinant yiFN to rats of surface expression of Thy 1 antigen. Exposure of also increased DC density in both the airway and lung Thy 1- (but not Thy 1•) lung fibroblasts to yiFN wall [77). stimulated surface la expression, and conferred on the In humans, chronic inflammation induced by cells the ability to present protein antigen to a specific cigarette smoking is associated with surface pheno­ T-cell clone [69]. It will be necessary to establish the typic changes and numerical increases in lung and capacity of these fibroblasts to present antigen to airway wall DCs, and increased frequency of intracyto­ freshly isolated T-cells which have not been adapted plasmic Birbeck granules, the presence of which indi­ to long term in vitro growth, before the significance cates DC activation [22]. DCs also contribute up to of this observation can be further assessed. 1.1% of BAL cells in smokers but <0.1% in controls [78], and comparable DC influxes have been observed in rats in response to local inflammatory challenge in B -lymphocytes the deep lung (see discussion [57]). As noted previously, B-cells function effectively An increased frequency of DCs has also been as APCs for restimulation of T-memory cells. reported in the nasal mucosa of allergic rhinitis Small numbers of B-cells are present in the lung wall sufferers during the pollen season [791, associated with and alveolar spaces in normal individuals, but there the presence of IgE on the surface of the cells. have been no reported formal studies on their APC In view of the postulated role of Fc-receptor-bound functions after extraction from lung tissue. lgE on DCs as an alternative pathway for allergen presentation to CD4•T-cells at sites of allergic inflam­ Intravascular cell populations mation [80], the possible presence of this antibody on the surface of lung DCs warrants further investigation. The extensive lung vascular bed contains a substan­ No information is currently available on the relative tial pool of transiently sequestered T-lymphocytes (see functional capacity of normal versus "inflammatory" discussion [70, 71]), a significant proportion of which DCs in the lung. appear to be in the process of division [72]. Accord­ ingly the theoretical possibility exists of local T-cell stimulation in response to blood-borne antigens, pro­ Mononuclear phagocytic cells (MPC) vided that local APCs are present. The available Ht­ eraturc suggests four potential candidates: transiently The first evidence that inflammation induced major sequestered B-cell blasts [73); cells from the marginal changes in regulation of T-cell activation in the lung monocyte pool [74); intravascular macrophages, ini­ stems from the original studies of MACKANESS [81] in tially thought to be restricted to ruminants [75] but the Listeria monocytogenes model in mice. He dem­ since demonstrated in humans [76]; and a sub­ onstrated that the induction of secondary T-cell medi­ population of intravascular DCs, thus far only ated immunity in the deep lung could not occur until described in rats [771. Given the potential conse­ the resident PAM population had been diluted by a quences of T -cell activation in this fragile micro­ large influx of blood monocytes [81], and suggested environment, the functional capacity of these cell that the latter provided a necessary source of active populations appear worthy of study. APCs to compensate for the functionally "defective" REGULATION OF APC FUNCTION IN AIRWAYS 125

PAMs. Our laboratory subsequently demonstrated that of PAM populations can increase in certain types in addition to failing to present antigen to T-cells, resi­ of infectious disease, notably tuberculosis [103], and dent PAMs actively suppressed T-cell proliferation human immunodeficiency virus (HIV) [104], but in and further showed that this suppression was reversed neither case was this associated with increased IL-l following the induction of a local inflammatory re­ production as with sarcoidosis. sponse which recruited fresh mononuclear cells for the blood [82]. Our original interpretation of these results, viz. that the active incoming cell was a monocyte, may Other cell types require revision in the light of the demonstration by Havernith and Hoefsmit (see discussion in [57]) that Increased e xpressio n o f c lass 11 MHC anti­ DCs are also present in alveolar mononuclear infil­ gens on mesenchymal cells in the lung is consistently trates in this animal model. reported throughout the literature on inflammatory dis­ Changes in macrophage populations have also been ease. As noted above, this may represenl a pathway reported in lhe context of inflammatory diseases in the for presentation of antigen-specific acti vating signals human lung. Acti ve recruitment or monocytes inlo to T-ce lls. but th e e me rg in g lile rature on reg­ the aiJway mucosu is a consistent finding in aslhma ulation of T-cell-recepror triggering points increasingly 183. g4 J, and in view of the known di ffere nces to the conve rse, viz. that activatio n by s u ch in cytokine producti on cnpacity of human monocy1es la .. "non· professional" APCs is incomplete, lacking compare d to ma ture pulmo nary mac rophages, the necessary (second) co-stimulutor signal required e.g. rssJ, such infiltration may contribute to the for proliferation and clonal expansion, and conse­ pathogenesis of rhe underl ying innammatory process. quently directs the T-ce LJ down a maturation pnthway No func tional dala are yet available on macro­ towards T-cell-receptor downregulation and anergy. phage fun ction(s) in asthmatic versu.1· normal airw•lYS While this represenu; an attractive ancillary protecti ve but several reports exist on BAL. Reported findings mechanism for dampening T-cell activily at inrlamma­ from comp,u·ati ve s1udies of normal 1•ersus atopic tory foci, formal proof of its operation in vivo is still BAL macropbages include equivalent: levels of prod­ lacking. uction of inlerleukio- 1 (IL- l) inhibitory factor f86J and Little is also known of the role of the B-cell arachidonic acid metabolites [87], increased numbers in T -cell activation in inflammatory diseases. B-cell of hypodense PAMs (suggestive of activation) in infiltration is not a significant feature of the inflam­ asthmatics [88], differing patterns of surface lectin­ matory process in the asthmatic airway wall [84], binding by astJ1matic PAMs [89]. depressed zymosan but traffic of these cells through inflammatory sites phagocytosis L9 0J, and decrea ·ed in vitm T -cell in other respiratory disease states could theoret­ inhibitory aclivity L9 1l by aslhmatic PAMs. In ically represent a source of antigenic signalling for addition, in vitro culwre of PAMs with corticosteroids adjacent draining lymph nodes. Again formal proof Uiied for treatment of asthmatics (via inhalation) has is lacking. been shown to modulate function-associated surface marker expression [92], but no formal data are yet available to indicate whether functional changes occur Conclusions in vitro or in vivo. More detailed information is available in pulmonary While the re are clearly a variety o r candidate sarcoidosis. The salient feature of this syndrome is APC populations for regulation ofT-cell activati on in excess T-helper activity a1 sites of disease acti vity in d iCferent tissue microenvironments in tlte lung and the lung f93 j, which is accornp:Ulied by a number of conducting air ways (summarized in ta ble 1), an surface phenotypic and fun ctional changes in adjacent overall picture is slowly emerging of how lhe major PAM popula1ions. These include increased surface cellular populations interact. Thus . under steady­ expression of class IT MHC r94-961 . enhanced capac­ state conditions, DC populations play a surveillance it y to present antigen to T-cells L97-99J, and enhanced role for incoming nntigens, shuttling them lo the drain­ ex pressio n o f surface antigens assoc iated with ing lymph nodes for evenlual presentalion lO the 1he monocytic end of the MPC differentiation spec­ T-cell system. and in disease free lung tissue they rep­ trum , cons iste nt with inc reased recruitme nt o r resent virtuall y the sole source of local APC acti vity. monocytcs from the peripheral blood r100] . Consist­ However, in response to inflammalory stimLtlation. ent with lhis suggestion, sarcoid PAMs secrete high the s pectrum of local cell ty pes expressing class £1 levels of lL- 1 f10J J analogous 10 monocytcs, whereas MHC is expanded via recruitment from the peripheral nonnal PAMs are poor producers of this cytokine rss]. blood and 11ia cytokinc-driveo "induction" of local These findings have prompted the s uggestion lhat mesenchymal cells, providing a range of optional alterations in the balance between inhibitory and :; ii mu­ APCs for upregulation and downregulation of local latory signals from the lung macrophage population T -cell respo nses. The balance be tween these may be an important aetiological factor in the en­ potential immunoregulatory APC p opulati ons are hanced local CD4• T-cell activity in this disease [100, undoubtedly key facto rs in the pathogenesis of 102]. immunoinflammatory diseases 1broughou1 the resp­ It has also been reported that the APC activity iratory system. 126 P.G. HOLT

Table 1 Potential antigen presenting cells in normal respiratory tract tissues Properties Dendritic Mature Monocytes Bronchial Type I! Fibroblasts B-cells cells macrophages epithelial alveolar cells eQithelium Class 11 MHC expression Constitutive ++++ ± + ++ Cytokine-induced ++ + ++ + + + + Distribution Airway epithelium +++* +++ Airway submucosa ++ +++* ±* + ± Alveolar wall ++ +* +* ++* + ± Airway lumen ± +++* ±* ± [Intravascular] [+] [+] [+) [+] APC activity I 0 immune responses ++++ ± ± 2° immune responses ++++** ++ [+] [+] ++ Anergy/suppresion ++ [?) [+] [?] Migratory capacity +++ + f?l + (to draining lymph nodes) Probable preferred Soluble ?articulate Particulate Soluble Small ? Soluble antigen(s) protein (baterial) (bacterial) protein particulates and (allergens?) Viruses Soluble Particulate Viruses proteins

*: increased in inflammation; **: normally only within the regional lymph node; [+): claim based on only a small number of observations, requiring verification; [?]: theoretically likely, but not presently known; MHC: major rustocompatability complex; APC: antigen presenting cells.

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