Regulation of adaptive immune responses by innate cells expressing ...

Regulation of adaptive immune responses by innate cells expressing NK markers and antigen-transporting macrophages J. Stein-Streilein,* K-H. Sonoda,* D. Faunce,* and J. Zhang-Hoover* *Schepens Eye Research Institute, Harvard Medical School, Boston; and †Pulmonary and Critical Care Division, Department of Medicine at Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Abstract: A continuing theme of work done in our laboratory involves regulation of adaptive immune response by innate cells, in general, and immuneregulation by natural killer (NK) and NKT cells, in particular. Studies include work with the lung and the eye. In addition to immune surveillance of tumor cells, the NK cell is often associated with secreting cytokines that contribute to the creation of microenvironments conducive to Th1 responses and with defense mechanisms that lessen the initial infecting viral load. Reported studies show that the NKT cells support both T helper cell responses (type 1 and 2), as well as their being absolutely central to the development of antigen-specific Tregulatory cells involved in peripheral tolerance. Because of the multifunctional capabilities of the NKT cell, we propose that yet another cell, such as the antigen-presenting cell (APC), may influence the effector pathway of the NKT cell. We postulate that the APC that transports the antigen from the entry environment provides both trafficking and activation signals for innate cells in the secondary lymphoid organs. Evidence is presented that macrophage-derived signals selectively recruit NKT cells and bias their cytokine synthesis. Data imply that, just as occurs in immune inflammation, a collection of innate and adaptive immune cells interact within the secondary lymphoid tissue to generate antigenspecific tolerance in the periphery. J. Leukoc. Biol. 67: 488–494; 2000. Key Words: inflammation · peripheral tolerance · pulmonary interstitial fibrosis · anterior chamber-associated immune deviation · influenza virus

INTRODUCTION Innate immune responses involve non-clonally derived defense cells that can respond immediately to danger [1, 2]. The defense mechanisms used by innate cells include regulatory mechanisms that contribute to the biasing of the clonally derived adaptive immune response. The relationship of the natural killer (NK) cell to the NKT cell is rarely studied, but the simple concept that the NK and NKT cell are in some sort of balancing 488

Journal of Leukocyte Biology Volume 67, April 2000

(yin-yang) relationship is sometimes implied [3]. It is well accepted that interferon-␥ (IFN-␥) promotes Th1 cellular immune responses [4–6], and the NK cell is an early and convenient source of this polarizing cytokine. Th2 cells appear to need interleukin-4 (IL-4) or IL-13 for their development, although the cellular source is unknown. Early studies suggested the NKT cell to be responsible for Th2 polarization, however, only a few experimental Th2 models depend on the NKT cell for IL-4 [7–9], because it was quickly revealed that several other models of Th2 responses still occurred in the absence of NKT cells [10–12]. At this time, the biological role for NKT cells is not fully understood. The role of the antigen-presenting cell (APC) is established in activation of immune inflammatory responses and adaptive immunity. However, the role of the APC in regulating other innate cell responses is less well understood. Evidence is presented that the antigen-transporting macrophages from local environments influence both innate and adaptive immune cells in the secondary lymphoid organs and influence whether inflammation or tolerance is the outcome. It has been known since the 1960s that regional spheres of immunological influence exist. At that time, the newly described IgA class of immunogloblin was shown to be particularly enriched in external bodily secretions such as tear, saliva, and intestinal contents. And, only 4 years later, it was shown that thoracic duct drainage contained recirculating lymphocytes passing through the lymph that were not homogeneous [13]. In fact, the IgA-bearing B lymphocytes were shown to preferentially localize in the gastrointestinal tract. Since that time, it was shown that antigen processing, and the subsequent immune responses in the gut and other mucosal tissues, was under the influence of the regional regulation and specialization [14, 15]. Studies in our laboratory support the notion of regional specialization in the lung [16]. Although the large airways are lined with mucosa and show some aspects of the mucosal immune system, the alveoli and air spaces are not part of the mucosal system and instead exhibit their own unique regulation to prevent immune responses and protect the lung’s physiological function of gas exchange.

Correspondence: Joan Stein-Streilein, Ph.D., Schepens Eye Research Institute, 20 Staniford St., Boston, MA 02114. E-mail: [email protected] Received November 4, 1999; revised January 19, 2000; accepted January 20, 2000.

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Role of NK cells in viral infections The NK cell was first noticed for its ability to kill tumor cells without prior sensitization, ergo its name [17]. We and others have shown that NK cells are critical for protection against certain viral infections [18–23]. It is important to note that NK cells limit the expansion of the viral load while T effector cells differentiate in response to viral antigens. Then, effector T lymphocytes complete the job by eliminating virus-infected cells [24]. In particular, we reported that NK cells were necessary for controlling the influenzal viral load in mice and hamsters because, in the absence of NK cells (eliminated in vivo with specific antibodies to antigens on the NK cell), infected mice expressed more virus and succumbed faster to the virus [20, 23, 25]. Furthermore, we and others carefully showed that, when given before virus infection, R␣AsGM1 treatment removed NK cells but did not remove effector T cells or macrophages [23, 26, 27]. Moreover, because the NK cell is present locally in a variety of tissues and organs, including the lung, methods were available to selectively eliminate the NK cells in the lung, leaving blood-borne NK cells intact [20, 25, 28, 29]. Thus, these studies showed that the NK cells that were protective were within the local environment. The idea that NK cell defenses were regulated locally contributed to the notion that regional specialization is an important concept in immune defense in the organism as a whole [15]. The concept that the NK cell in the lung, and more recently, the NKT cell (see below), are part of regional specialization mechanisms is well supported by recent work on NK and NKT cells in the liver [30, 31].

NKT cells NKT cells make up a subpopulation of nontraditional T cells that co-express NK markers and were first studied for their ability to initiate polarization of the T helper cell responses [32, 33]. Details of this cell are published elsewhere [31, 34–36]. The novel lymphoid lineage that gives rise to NKT cells produces lymphocytes that are distinct from other lymphoid cells, including T, B, and NK cells. The majority of NKT cells in the mouse co-express NK markers and a single invariant T cell receptor (TCR) encoded by the V␣14 and J␣281 gene segments [37–39] in association with a highly skewed set of V␤s [40–47]. Moreover, the generation of V␣14 J␣281 TCRNKT cells is exclusively dependent on the expression of the invariant V␣14 J␣281 TCR as evidenced by the fact that these cells do not develop in the invariant J␣281-deficient mice [48], and that the forced expression of the invariant V␣14 TCR led to expression of exclusively V␣14 NKT cells conventional T cell development [49, 50]. The invariant T cell receptor on a subpopulation of NKT cells binds CD1 with or without lipids [51]. A ligand for the invariant V␣14V␤ 8.2 TCR exclusively expressed on V␣14 NKT cells has been identified recently to be ␣ galactosylceramide (␣ GalCer) [52]. In addition, ␣ GalCer is presented by a monomorphic major histocompatibility gene complex (non-MHC) class I molecule, CD1.d, expressed on dendritic cells and other bone marrow-derived cells. The ligand/CD1 complex selectively stimulates V␣14 NKT cells, but not other lymphocytes, to proliferate [53, 54]. Thus the invariant V␣14V J␣281 TCRexpressing NKT cell subpopulation is CD1.d restricted. V␣14

J␣281 TCR is found on up to 85% of NKT cells [51, 55]. Unlike the human, which expresses CD1.a, b, c, and d, the mouse only expresses CD1.d. Moreover, human NKT cells that express the invariant V␣ 24J␣Q invariant TCR also bind to CD1.d [56]. Therefore, the CD1-restricted mouse models exploiting CD1/ NKT cell interactions are directly relevant to the function of human NKT cells [55].

Cytokine production in NK and NKT cells during regional immune responses Recent work in our laboratory analyzed cytokines produced by NK and NKT cells in several experimental animal models involving lung and eye immunology [57, 58]. In the lung we observed that NK cells within the alveolar spaces produced IFN-␥ during toxicity (bleomycin)-initiated inflammatory processes and immune-mediated inflammatory responses [hapten immune pulmonary interstitial fibrosis (HIPIF)] [59]. In contrast, NK cells were essentially absent in the bronchoalveolar lavage samples during the Th2-mediated inflammatory process found to be dominant in the mouse ovalbumin (OVA)-asthma lung model [57]. On the other hand, NKT cells were prominent in all three models of immune inflammation in the lung; albeit they displayed different intracellular cytokine profiles [57]. NKT cells containing IL-4 were increased in the OVA-asthma model, whereas NKT cells synthesizing IFN-␥ [60] were prominent in the inflammatory or Th1-initiated fibrotic animal models. Thus, as suggested by others, the NKT cell is quite pleotropic in its responses [48, 61–63]. Because the NKT cell responds to primary stimulation in a variety of ways, we reasoned that yet another cell might orchestrate the response seen in the NKT cell. We postulated that the antigen-transporting macrophage from the local environment of antigen entry may influence the subsequent innate and adaptive immune response. Evidence is published that supports the notion that antigen-transporting macrophages derived from the eye are important to the development of the immune deviation or peripheral tolerance that occurs during the development of anterior chamber-associated immune deviation (ACAID) [64, 65].

ACAID model of peripheral tolerance The model for ACAID is an established protocol for the study of mechanisms that induce peripheral tolerance in response to antigen injected into an immune-privileged site, such as the eye [66–68]. Published data show that eye-derived APCs identified by F4/80⫹ expression leave the eye by 3 days post-inoculation, travel through the blood as an ACAIDinducing signal, and settle in the spleen thereafter [69]. The F4/80⫹ cell, being influenced by the suppressive microenvironment of the anterior chamber, is specialized and produces transforming growth factor ␤ (TGF-␤), which induces autocrine production of TGF-␤ in the cells it binds [64, 65, 70]. Thus the antigen-transporting macrophage from the environment of antigen entry influences both the innate and adaptive immune response that occurs in the secondary lymphoid organ. During the ACAID induction process in the spleen, antigen is thought to be presented to CD8⫹ T cells that then differentiate into antigen-specific negative regulatory cells [70]. The signals that

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influence the differentiation of CD8⫹ T cell into regulatory cells are not clearly defined. In part, the role of NKT cells in development of peripheral tolerance contributes to a better understanding of T lymphocyte regulatory cell development [58]. Initially, we observed that an accumulation of NKT cells in the spleens of anterior chamber-inoculated mice was associated with the development of CD8⫹ T regulatory cells during ACAID induction [58]. The detection of NKT cell accumulation in the spleen was reproducible and was observed in C57BL/6 (B6), BALB/c, and (B6 ⫻ 129) F1 strains of mice during ACAID induction (Table 1).Thus it is unlikely that NKT cell accumulation in the spleen during ACAID is dependent on a particular genetic background.

Requirement for CD1/NKT cell interaction in ACAID-induced peripheral tolerance To test the role of NKT cells in the development of ACAID, we used CD1 knockout (KO) mice as hosts for the model. The CD1 KO mice used (developed by S. Balk and colleagues at Beth Israel-Deaconess Medical Center, Boston, MA) lack both genes for CD1 and, it is important to note, lack NKT cells because the CD1.d that is expressed by cortical thymocytes is needed for positive selection of the major subpopulation of NKT cells [71, 72]. Indeed, CD1 KO mice were unable to develop T regulatory cells specific for the antigen ovalbumin after anterior chamber inoculation unless the mice were first reconstituted with wild-type NKT cells [58]. The model of ACAID can be recreated in part or in full in vitro [73–75]. Partial in vitro ACAID requires that APCs [in this case, thioglycolate-induced peritoneal exudate cells (PECs)] be pulsed with antigen in the presence of TGF-␤ before being inoculated intravenously into a naive mouse to induce peripheral tolerance. Previously it was noted that TGF-␤-treated PECs down-regulate CD40 and IL-12 expression [76]. We observed that OVA-pulsed PECs that were treated with TGF-␤ responded, in part, with increased expression of their CD1 molecules (Fig. 1). Therefore, we predict that eye-derived APCs in vivo also express more CD1 molecules per cell because of their exposure to TGF-␤ in the aqueous humor. We presume that when NKT cells bind to CD1 on the APC, the NKT cells are stimulated to produce immune-suppressive cytokines (TGF-␤ or IL-10) that in turn contribute to the differentiation of the CD8⫹ precursor T cells. Because there is no intracytoplasmic portion of the CD1 molecule, the CD1expressing cell is thought to not receive signals when the CD1 molecule is engaged [77]. Published results show that when TABLE 1.

Number of NKT Cells in the Spleen After Anterior Chamber Inoculation of Ovalbumina,b Mouse strain

Treatment

AC-HBSS AC-OVA

C57BL/6

BALB/c

17,589.8 ⫾ 1652.6 34,528.8 ⫾ 3542.1c

14,480.8 ⫾ 313.1 23,150 ⫾ 2340.7c

a Data are represented as mean number of NKT cells per 1 ⫻ 106 spleen cells ⫾ SEM. b NKT cell counts were performed 7 days after anterior chamber inoculation. c Significant from anterior chamber-HBSS-treated group when P ⬍ 0.05 as determined by ANOVA.

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Fig. 1. Flow cytomertry analysis of CD1.d expression in TGF-␤-treated PECs. PECs were obtained from peritoneal washes of mice 3 days after they received an intraperitoneal inoculation of 2.5 mL of 3% aged-thioglycolate solution (Sigma Chemical, St. Louis, MO). After counting, PECs (2 ⫻ 106) were cultured with OVA (5 mg/mL), with and without porcine TGF-␤2 (5 ng/mL, R & D Systems, Minneapolis, MN) in a 24-well culture plate in serum-free medium [RPMI 1640 medium, 10 mM HEPES, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 100 U/mL penicillin, 100 µg/mL streptomycin (Biowhitaker, Walkersville, MD), and supplemented with 0.1% bovine serum albumin (Sigma), ITS⫹ culture supplement (1 µg/mL iron-free transferrin, 10 ng/mL linoleic acid, 0.3 ng/mL Na2Se, and 0.2 µg/mL Fe (NO3)3, Collaborative Biomedical Products, Bedford, MA)]. Nonadherent cells were removed form the cultures after 24 h by washing and the remaining adherent cells were collected by vigorous pipetting with cold phosphate-buffered saline (4°C) before washing with HBSS to remove free OVA and TGF-␤2. TGF-␤2-treated or nontreated PECs were double stained with phycoerythrin-conjugated Mac-1 (M1/70.15, Caltag, South San Francisco, CA), biotin-conjugated anti-CD1.d (1B1, PharMingen, San Diego, CA) counterstained by SA-fluorescein isothiocyanate (PharMingen). Stained cells were analyzed on an EPICS XL flow cytometer (Beckman Coulter, Miami, FL). Total Mac-1-positive cells (8 ⫻ 103) were gated, and surface CD1.d expression was evaluated.

CD1 interaction with NKT cells is blocked in vivo with CD1-specific antibodies, CD8⫹ T regulatory cells do not develop. Of course, we do not know whether the CD1 on the eye-derived APC is the only CD1 molecule to which the TCR on the NKT cell binds. NKT cells could bind CD1 on CD8⫹ T cells, B cells, as well as stromal cells. The novel idea of a cluster of cells being required for the induction of peripheral tolerance is being explored.

Chemokines, NKT cells, and tolerance Chemokines make up a large family of small proteins that are known to play a critical role in immune and inflammatory reactions and in viral infections and are reviewed elsewhere [78–82]. Chemokines are made predominantly by myeloid-derived cells. Usually the chemokines share receptors, and many have overlapping functions. In addition to recruitment, several recent reports now attribute a variety of nontrafficking biological functions to these small cytokine molecules. Both the role of chemokines in the development or maintenance of tolerance and the effects of chemokines on NKT cells are unexplored areas. Recently, we turned our attention to the question of how NKT cells accumulate in the spleen during ACAID. They could http://www.jleukbio.org

Fig. 2. Kinetics of MIP-2 production and NKT cell accumulation in blood and spleen after anterior chamber OVA. Accumulation of NKT cells in the spleen after anterior chamber inoculation of OVA correlates with the kinetics of F4/80 and MIP-2 mRNA expression in the spleen (solid areas). Total cellular RNA was isolated from blood monocytes and splenic adherent cells (macrophages) at various times after anterior chamber inoculation of OVA. MIP-2 mRNA expression was examined with a multiprobe RNase protection assay and quantified by phosphorimaging and densitometry. The frequencies of splenic F4/80⫹ and NK1.1/TCR␤⫹ (NKT) cells were determined by flow cytometry. Note that shortly after anterior chamber OVA, MIP-2 mRNA can be detected among blood monocytes, but disappears from the blood and then appears in the splenic macrophage population at 1 week after anterior chamber OVA, suggesting that MIP-2-producing cells traffic via the blood to the spleen. The trafficking of MIP-2-producing cells from the blood to the spleen resembles that of the F4/80⫹ cell (hatched bar) and NKT cell (checked bar) accumulation. The up-regulation of MIP-2 and appearance of F4/80⫹ cells and NKT cells is unique to the induction of peripheral tolerance in the spleen after antigen inoculation in the eye.

proliferate or be recruited. We postulated that NKT cells were recruited by a select group of chemokines. Recent evidence showed that macrophage inflammatory protein-2 (MIP-2; mouse IL-8 analog) and IP-10 were selectively up-regulated in both in vitro-treated ACAID-conferring-macrophages and the mono-

cytes/macrophages in the peripheral blood of mice 3 days post anterior chamber inoculation [83]. It was interesting to us that the kinetics of the MIP-2 expression from the blood monocytes to splenic adherent cells mimicked the path of the F4/80⫹ cell, noted previously by Wilbanks and Streilein [64, 65] to be the ACAID-inducing signal (Fig. 2). Boyden chamber studies showed that MIP-2 was a chemoattractant for NKT cells and not for other lymphocytes tested [83]. As expected, NKT cells expressed the CXCR2 receptor (data not shown). Moreover, MIP-2-neutralizing mAb, given systemically, effectively blocked the recruitment of the NKT cells to the spleen and the subsequent differentiation of the CD8⫹ T regulatory cells and therefore prevented the induction of peripheral tolerance [83]. We now postulate that the involvement of MIP-2 in tolerance induction is not a response unique to antigens injected into the eye, but will be a general mechanism used in other immuneprivileged sites as well as organs and tissues when CD8⫹ T regulatory cells are generated to suppress expression of immune responses.

DISCUSSION In summary, reports by our laboratory showed that NK cells provided cytokines (IFN-␥) that helped to clear influenza virus (and other viruses) and contributed to the biasing of the immune response toward a Th1 response [22, 84, 85]. During pulmonary conditions in which the Th1 response was chronic or the toxicity of the chemical led to the release of inflammatory cytokines, the NK cell contributed to the pathophysiological state of the organ by promoting an inflammatory response through its IFN-␥ release. Others reported that, under other conditions, the NK cell can make Th2-type cytokines in the absence of IFN-␥ [15]. On the other hand, in our animal models, the NKT cell was prominent in both Th1 and Th2 responses, as well as being critical to the development of peripheral tolerance to the eye-inoculated antigens. In both mouse and human a major

Fig. 3. Model for role of NKT cells and antigentransporting macrophage in spleen during ACAID. The model shows that APCs (derived from the eye) selectively up-regulate chemokines capable of attracting NKT cells. Then, NKT cells brought to the spleen by MIP-2, bind CD1 expressed on APCs. TCR binding to CD1 may induce NKT cells to synthesize and secrete chemokines that recruit CD8⫹ T cells to the site of tolerance induction. The cluster of cells participating may include APCs, CD8⫹ T cells, B cells, and NKT cells. The cells could be held together by CD1 and other unknown adhesion molecules. The NKT cell, stimulated through its TCR by CD1 ligation, produces regulatory cytokines (IL-10, TGF-␤) that in turn influence the differentiation of CD8⫹ T cells into negative regulatory cells for delayed-type hypersensitivity (DTH) and peripheral tolerance induced via the eye.


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subpopulation of NKT lymphocytes responds to signals provided ligation of its TCR to CD1 molecules [51, 56]. It is possible that the CD1-induced signals in NKT cells may depend on the character of the antigen-transporting APC that expresses it (i.e., TGF-␤ versus IL-12 secretion). In addition, the transporting APC may express critical co-receptors (or cytokines) for activation of NKT cell secretion of inflammatory cytokine (IFN-␥ that are different or absent from the antigentransporting APCs that signal the NKT cell to secrete downmodulatory cytokines and support the development of Tregulatory cells. Others showed that the cytokine microenvironment that is present during the binding of the NKT cell to the CD1 molecule will influence the type of cytokine produced by the NKT cell [48, 61, 63]. Understanding the subtle differences among the signals received by NKT cells through CD1 ligation on antigen-transporting macrophages might lead to new knowledge and therapies in conditions where there is a breakdown in tolerance (autoimmunity). Recent studies [83] showed a unique profile of chemokines that was responsible for recruitment of NKT cells during peripheral tolerance induction in the spleen after the antigen was inoculated into an immune-privileged site. Recruitment of the appropriate cells to the secondary lymphoid organ for tolerance supports the concept of required cellular interactions dependent on chemokines and ligands different from those that encourage the promotion of cell clusters required for activation and induction of inflammation (Fig. 3). The model for immuneprivileged site-induced tolerance is equally applicable as a model of self-tolerance in tissues and organs. Generation of negative regulatory T lymphocytes may be defective in certain autoimmune diseases. Reports of an association of defective or deficient NKT cells in a variety of autoimmune diseases in both mouse and humans have been published [86–90]. Moreover, diabetic-prone NOD mice were protected from the onset of diabetes with the adoptive transfer of NKT cells [90, 91]. The phenotype of such NKT cells is not well described, but it is assumed that the protective NKT cells must prevent the Th1-destructive environment and would imply, therefore, that there may be a role for NKT cell-induced antigen-specific CD8⫹ T regulatory cells in the prevention of diabetes and other autoimmune diseases.

ACKNOWLEDGMENTS Dr. Douglas Faunce is a recipient of the National Eye Institute National Research Service Award 1 F32 EY07021-01; and Dr. Jie Zhang-Hoover is a recipient of the National Heart Lung and Blood Institute National Research Service Award 1 F32 HL10148-01A1. This work was supported in part by National Heart Lung and Blood Institute Grant R01 HL 33709-09, National Eye Institute Grant R01 EY1 EY11983-01A2, and The Schepens Eye Research Institute. We thank Drs. J. Wayne Streilein, Steven P. Balk, and Mark Exley for their helpful discussions on ideas and concepts presented in this review. We also appreciate Ms. Gayle Barry’s efforts in preparing the manuscript. 492


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