Regulation of Helper T Cell Differentiation and Recruitment in Airway Inflammation

FRANCESCO SINIGAGLIA and DANIELE D'AMBROSIO

Roche Milano Ricerche, Milan, Italy

	ABSTRACT

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CD4⁺ helper T type 1 (Th1) and Th2 cells are critical mediators of inflammatory diseases. Although T cells represent only a fraction of the leukocytes that are found in the lung during inflammation, they play a critical role in coordinating the immune response to infectious agents and allergens. T cells have the ability to rapidly expand in response to specific stimuli and to differentiate into effector cells that, through the production of soluble factors such as cytokines and chemokines, communicate with other cells to initiate a cascade of inflammatory events. The objective of this review is to outline the cellular and molecular mechanisms involved in the generation and recruitment of Th1 and Th2 cells in the lung. Defining these mechanisms should lead to improved immunopharmacological strategies for prophylaxis and therapy.

	INTRODUCTION

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Helper T type 1 (Th1) cells are characterized by secretion of interferon  (IFN-) and tumor necrosis factor (TNF) and are adept at macrophage activation and immunoglobulin selection for isotypes that mediate antibody-dependent cellular cytotoxicity and complement activation (1). Thus, Th1 cells have the ability to activate appropriate host defenses against intracellular pathogens but can also cause tissue damage if dysregulated (2). In the lung, Th1-dominated responses result in a neutrophil-predominant inflammatory response. Th2 cells, in contrast, produce interleukin 4 (IL-4), IL-5, and IL-13, which promote IgE production and eosinophil function, both of which play a role in the pathogenesis of asthma. Indeed, many studies have shown that eosinophilic inflammation associated with hypersecretion of mucus, is dependent on the presence of Th2 cells in the lung (3).

	ROLE OF CYTOKINES AND APCs IN THE DEVELOPMENT AND REGULATION OF HELPER T SUBSETS

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Induction of the type 1 or 2 response involves many factors, including the genetic background, the costimulatory signals, and the nature of the antigenic stimulus. It is clear, however, that the most important factor influencing this process is the type of cytokines present in the T cell microenvironment during antigen presentation and initiation of the T cell response. IL-4 and IL-13 promote Th2 development, whereas IL-12 and IFNs play a central role in controlling the development of Th1 cells from naive precursor T cells (reviewed in Reference 4). Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) for Th cells and instruct the T cells, via the secretion of cytokines such as IL-12, to differentiate along the Th1 or the Th2 pathway. The environment in which the DC has been stimulated, the type of stimulus, and the origin of the DC all play a part in the fate of the T cell response. Studies indicate that respiratory tract DCs have an immature phenotype expressing a low level of MHC class II molecules on their surface and producing IL-10 but minimal IL-12, thus favoring Th2 differentiation (5). In contrast, mature DCs isolated from peripheral lymphoid organs produce elevated levels of IL-12 and thus stimulate the generation of Th1 cells (Figure 1). Th1 cells can be generated in the respiratory tract when the appropriate stimulus is provided. For example, pathogenic organisms that require macrophage activation for host defense, such as Mycobacterium tuberculosis, stimulate IL-12 production by APCs, resulting in Th1-dominated, cell-mediated immune response. In addition to the maturation state of the DC, in vitro and in vivo data suggest that IL-12 production by DCs can also be modulated by microenvironmental tissue factors, as well as pharmacological agents. Prostaglandin E₂ (PGE₂) (6), ₂-agonists (7), 1,25(OH)₂-vitamin D₃ (8), histamine (9), and nitric oxide (10) have all been identified as inhibitors of IL-12 production and thus favoring Th2 differentiation. Taken together, these findings support the theory that induction of either Th1 or Th2 differentiation depends on the DC maturation state and on the influence of several factors on the ability of DCs to produce IL-12.

View larger version (38K): [in this window] [in a new window]   Figure 1.   Regulation of helper T cell differentiation. Differentiation along the Th1 or Th2 pathway is triggered by stimulation with the antigen-MHC complex presented by the appropriate antigen-presenting cell (APC). Among the APCs, the mature dendritic cell (DC1) produces IL-12 that drives Th1 differentiation. The immature DC (DC2), in contrast, does not produce IL-12, thus providing a permissive environment for Th2 differentiation.

	MOLECULAR BASIS OF Th CELL DIFFERENTIATION

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The STAT (signal transducers and activators of transcription) factors STAT4 and STAT6, induced by IL-12 and IL-4, play a crucial role in mediating the differentiation of naive T cells: STAT4 is necessary for Th1 differentiation induced by IL-12 (11, 12) and Type I IFN (13) and STAT6 is required for Th2 differentiation driven by IL-4 and IL-13 (14, 15). Developmental commitment to the Th2 lineage results from rapid loss of IL-12 signaling in Th2 cells (16). The inability of Th2 cells to respond to IL-12 appears to be due to selective downregulation of the IL-12 receptor (IL-12R) 2 subunit (17). Inhibition of Th1 and induction of Th2 in vivo are also related to downregulation of IL-12R 2 subunit expression (20). Modulation of chromatin structure also regulates cytokine gene expression during T cell differentiation (21). Differentiation of naive helper T cells into mature Th2 cells is associated with chromatin remodeling of the IL-4 and IL-13 genes, whereas differentiation into Th1 cells involves selective remodeling of the IFN- gene. IL-4 locus remodeling is accompanied by demethylation, with the acquisition of a characteristic open chromatin structure. This could lead to occupancy of the accessible DNA by specific transcription factors such as GATA-3 (22) and c-Maf (23) in Th2 cells. A similar model can be envisaged for Th1 gene expression, although much less information is presently available for Th1-specific transcription factors that could operate downstream to STAT4.

	MECHANISMS FOR RECRUITMENT OF EFFECTOR T HELPER CELLS INTO THE LUNGS

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The recruitment of Th1 and Th2 cells into the lung plays an essential role in regulating the inflammatory host response to infectious agents as well as allergens. Localization of inflammatory cells into the lung requires specific interactions with the vascular endothelium and subsequent migration of cells through the vessel wall and within the tissue. Leukocyte extravasation is a multistep process mediated by the interplay of adhesion molecules, chemokines, and chemokine receptors that involves rolling, firm adhesion, diapedesis, and migration within interstitial tissues (24, 25). Thus, in the lung the selective recruitment of Th1 or Th2 cells and other inflammatory cells is dictated by the combination of specific trafficking signals expressed on the endothelium and within the interstitial tissue.

Studies from our group and others have pointed out that among trafficking signals, chemokines and their receptors provide a central paradigm for understanding the mechanisms regulating the tissue-specific recruitment of Th1 and Th2 cells (26). Chemokines are members of a large, growing family of small cytokines, which play a key role in the leukocyte recruitment process (27, 28). The relative positions of a cysteine tandem defines four structural motifs (CXC, CC, C, and CX3C). These molecules exert most of their biological effects by binding to a large family of G protein-coupled seven-transmembrane receptors (10 CCR, 5 CXCR, 1 CX3CR, and 1 CR) leading to activation of multiple intracellular signaling pathways. Given the elevated number of ligands and receptors, the chemokine system is well suited to provide the diversity of signals needed for the exquisite specificity of the leukocyte recruitment process. Besides promoting cell adhesion and migration by regulating integrin function, chemokines have been reported to regulate cellular proliferation, differentiation, and apoptosis (29, 30).

	CHEMOKINE RECEPTORS ON EFFECTOR Th1 AND Th2 CELLS

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We and others have reported differential expression of several chemokine receptors on Th1 and Th2 cells (31) (Figure 2). Th1 cells have been shown to preferentially express CCR5 and CXCR3, whereas Th2 cells were reported to preferentially express CCR3, CCR4, and CCR8. Selective expression of chemokine receptors results in differential chemotactic responsiveness of Th cells. Macrophage inflammatory protein 1 (MIP-1) (CCR5 ligand) and interferon-inducible protein 10 (IP-10) (CXCR3 ligand) attract preferentially Th1 cells, whereas eotaxin (CCR3 ligand), I-309 (CCR8 ligand), macrophage-derived chemokine (MDC), and thymus and activation-regulated chemokine (TARC) (CCR4 ligands) attract predominantly Th2 cells. Studies have shown that some of these receptors are expressed in vivo by effector T cells infiltrating the inflamed lung tissue. In human sarcoidosis, a typical Th1 cell-mediated lung disease, the T cells isolated from the lung express high levels of CXCR3 (35). The eotaxin receptor CCR3, which is reportedly expressed by Th2 cells and eosinophils (33, 36), has been strongly implicated in the pathogenesis of allergic asthma (37, 38). Studies performed in a mouse model of allergic lung inflammation have documented CCR4 expression on lung-infiltrating Th2 cells and have documented a role for this receptor in the pathogenesis of airway hyperresponsiveness (39, 40). Overall, these findings support the theory that at least some of the chemokine receptors differentially expressed by Th1 and Th2 cells play an important role in localization of effector T cells into the lung and in the pathogenesis of different lung diseases.

View larger version (24K): [in this window] [in a new window]   Figure 2.   Differential expression of chemokine receptors in Th1 and Th2 cells. Unlike naive T cells, CD4+ effector T cells express a broad range of chemokine receptors, some of which are preferentially expressed on Th1 cells (CXCR3 and CCR5) versus Th2 cells (CCR3, CCR4, and CCR8) (31).

Findings have demonstrated that several receptors for inflammatory chemokines such as CCR1, CCR2, CCR3, CCR5, and CXCR3 are downregulated after T cell receptor (TCR) triggering of Th1 and Th2 cells. In marked contrast, CCR7, CCR4, and CCR8 are strongly upregulated on TCR-mediated activation (Figure 3) (41). These changes in chemokine receptor expression may serve to modify the migratory behavior of activated Th cells and establish a hierarchy of action among distinct chemokine-receptor axes. For instance, it is feasible that CCR3, CCR4, and CCR8 may regulate the extravasation of circulating Th2 cells and, on activation, their relocalization in the tissue microenvironment. On this subject, it is noteworthy that in the study by the group of Gutierrez-Ramos, the MDC-CCR4 axis was shown to act by retaining inflammatory cells within the lung tissue without affecting their extravasation (39, 40). Furthermore, the reported modulation of chemokine receptor expression in response to a variety of cytokines may be another way to target specialized Th cell subsets to specific microenvironments (42). On the one hand, this extreme plasticity of expression suggests that inhibiting the action of these chemokine receptors may be useful in multiple pathological settings. On the other hand, it also makes these receptors unlikely to serve as selective markers of disease.

View larger version (41K): [in this window] [in a new window]   Figure 3.   TCR-mediated activation (CD3/CD28) induces the downregulation of receptors for inflammatory chemokines, whereas receptors such as CCR7, CCR4, and CCR8 are upregulated. CCR8 and CCR4 are expressed at low levels (gray color) on resting Th2 cells and on activated Th1 cells, respectively (41).

	CHEMOKINE EXPRESSION IN THE LUNG

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Almost any cell type under appropriate conditions produces chemokines. The lung tissues are no exception, and several chemokines are produced either constitutively or during the course of an inflammatory process. Several studies have provided an initial picture of the complex role that different chemokines play in the pathogenesis of asthma. Eotaxin was found to be upregulated in the airways of patients with allergic asthma (37, 38). This chemokine, by binding to the CCR3 receptor, is likely to promote the recruitment and colocalization of eosinophils and Th2 cells to sites of allergic inflammation. As discussed in the previous section, MDC has been implicated in the pathogenesis of airway hyperresponsiveness. However, several chemokines are upregulated in the asthmatic lung and are potentially implicated in the pathogenesis of allergic asthma (43). Both inflammatory and stromal cells are likely to contribute to the overall production of chemokines (44). In the near future, it will be important to identify the kinetics and discern the sources of chemokines to understand the causal relationship between waves of chemokines and the evolution of the inflammatory process in vivo. The production of chemokines by inflammatory cells, T cells in particular, may play a critical role in the evolution of the immune response in the allergic lung. On this subject, we have reported that TCR-activated Th1 cells can produce the Th2 cell-attracting chemokines MDC and I-309 and that this production is inhibited by IL-12 (45). It is therefore tempting to speculate that the secretion of these Th2 cell-attracting chemokines by activated Th1 cells may favor the recruitment of Th2 cells (Figure 4). Intriguingly, studies performed with animal models of allergic airway inflammation suggest that Th1 cells are recruited early during the allergic response, whereas Th2 cell recruitment occurs later and is facilitated by Th1 cells (46, 47). Furthermore, these studies challenge the view that allergic asthma is a purely Th2 cell-mediated disease, and instead suggest that Th1 cells can cooperate with Th2 cells to aggravate the clinical manifestations of the disease. This may help explain why viral infections are among the most common triggers of an asthma attack.

View larger version (72K): [in this window] [in a new window]   Figure 4.   A schematic view of the potential homeostatic role that chemokines, such as MDC and I-309, produced by activated Th1 cells, may play by recruiting Th2 cells (45).

	Footnotes

Correspondence and requests for reprints should be addressed to F. Sinigaglia, M.D., Roche Milano Ricerche, via Olgettina 58, I-20132 Milan, Italy. E-mail: francesco.sinigaglia{at}roche.com

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