key: cord-0036876-cpdpinsv
authors: Lukacs, Nicholas W.; Schaller, Matthew
title: Lymphocyte trafficking and chemokine receptors during pulmonary disease
date: 2006
journal: Lymphocyte Trafficking in Health and Disease
DOI: 10.1007/3-7643-7442-x_7
sha: 408a7e1545f8b06f4c9e7431ed4c00804894c37e
doc_id: 36876
cord_uid: cpdpinsv

nan

The localization of lymphocytes to tissue during immune/inflammatory responses involves a series of complex mechanisms, including activation of integrin binding, adhesion molecule expression, and tissue-based chemokine production. The regulation of specific molecules and the expression of certain receptors on lymphocytes during the progression of disease determine the type of T lymphocytes, Th1 or Th2, which migrate into the tissue. Although there have been studies that have outlined tissue-specific expression of certain chemotactic molecules, a more logical view may be that the type of immune/inflammatory response induced within the affected tissue would dictate the mediators that are expressed. The trafficking of naive lymphocytes from the blood to lymph nodes is pivotal to the maintenance of effective immune surveillance; however, deciphering the mechanisms involved in lymphocyte recruitment during inflammation may be more pharmaceutically attractive for regulation of chronic debilitating diseases. Functional diversity of T cells has been demonstrated by the observation that naive T lymphocytes are activated and differentiate into Th0 type cells that produce different combinations of cytokines. Subsequently, these cells can further differentiate into either Th1 type cells (IL-2 and IFN) or Th2 type cells (IL-4, IL-5, and IL-13) depending upon the cytokine environment to which the Th0 cells are exposed [1, 2] . Over the years, it has become clear that certain diseases are characterized by the T helper (Th) cytokine phenotype that is produced. In particular, allergy and asthma responses have been identified as a largely Th2-type disease [3, 4] . The following review outlines some of the recent concepts that may dictate how and why certain Th lymphocyte subsets migrate into inflamed tissues and what contributions other disease mediators provide to worsen the disease process.

The migration of lymphocytes into tissues appears to be dependent upon the expression of specific chemokines during the progression of the inflammatory disease. Chemokines are a family of small molecular weight cytokines that are important for localization of particular leukocyte populations during immune/inflammatory responses [5] [6] [7] . Chemokines are primarily divided into two main groups, CxC and CC, based upon the juxtaposition of the first two-cysteine residues in their sequence (Tab. 1). The responses induced by the chemokines are initiated via specific G protein-coupled receptors on the surface of cells. Although not entirely characterized, it appears that there are no less than six different CxC family receptors and ten different CC family receptors. In the context of allergy, members of the CC subfamily have been implicated as potential mediators of the inflammatory response through their ability to induce migration of eosinophils, T cells and monocytes. In addition to playing a prominent role in the localization of leukocytes to tissue sites, these activating factors are also involved in important biological events, such as eosinophil and mast cell degranulation, differentiation of Th lymphocyte phenotypes, and regulation of antibody isotype switching. Thus, these molecules have important functions in multiple phases of the developing immune response.

Some of the initial studies in chemokine biology outlined the role of early response cytokines, such as TNF and IL-1, for the activation of chemokines [8] . These early studies reported that chemokines could be induced in nearly every cell type. Subsequently, investigators have begun to define the association of certain chemokine profiles with particular types or phases of immune responses. In fact, the preferential expression of certain chemokines during immune responses likely dictates their function [9] [10] [11] . For example, the CC chemokine family members, CCL3 and CCL5, are induced by IFN and TNF, but regulated by IL-4, and appear to be closely associated with Th1-type responses. Likewise, the production of CxCR3 ligands, CxCL9, CxCL10, and CxCL11, are specifically activated by IFN and may have critical roles in enhancing Th1-type lymphocyte recruitment and activation. Along with the preferential expression of chemokines during Th1-type responses, there is also the preferential expression of the associated chemokine receptors on Th1-type lymphocytes. A number of studies have shown the preferential expression of CCR1 and CCR5 (which binds CCL3 and CCL5) as well as CxCR3 (which binds CxCL9, CxCL10, and CxCL11) on Th1-type lymphocytes. Thus, the chemokine expression during a Th1-type response correlates directly with the specificity of the chemokine receptors that are expressed on Th1-type lymphocytes.

As there are chemokines associated with Th1-type responses, there also appears to be certain chemokines that are closely associated with Th2-type responses [9, 12, 14] . An extensive amount of work was performed on CC chemokines, and particular members of this family are specifically activated by IL-4 and IL-13 [15] [16] [17] [18] [19] . The CC chemokines that are preferentially up-regulated by Th2-, but not Th1-, type cytokines include CCL1, CCL2, CCL11, CCL17, and CCL22. Interestingly, these IL-4-and IL-13-induced chemokines bind to a single chemokine receptor (see Tab. 1), which is fairly unusual among chemokine family members that tend to have a promiscuous binding pattern to multiple chemokine receptors. Studies have indicated that CCL2 is involved in allergen-induced T lymphocyte accumulation in the lungs of sensitized mice, whereas CCL11 is most closely associated with eosinophil accumulation during allergic responses. Thus, the Th2 activation pathway, which has been associated with allergen-induced airway hyperreactivity, likely induces preferential chemokine production that is associated with allergic cell recruitment. This area will be of particular interest since studies have previously shown that these Th2-associated chemokines play significant roles in allergen-induced airway inflam-117 Lymphocyte trafficking and chemokine receptors during pulmonary disease mation and airway hyperreactivity. Furthermore, analysis of in vitro-derived Th2type cells indicates preferential expression of CCR3 (CCL11), CCR4 (CCL17, CCL22) and CCR8 (CCL1) [12, [20] [21] [22] [23] . This receptor expression pattern correlates well with the type of chemokines that are induced by Th2-type responses discussed above. In addition to lymphocyte migration, there is also preferential chemokine receptor expression on effector cells that migrate into the airways and can induce damage, leading to airway hyperreactivity. Overall, the recruitment of multiple cell populations into allergic tissue is mediated by a combination of preferential chemokine production within the inflamed tissue and the receptors expressed on the marginated leukocyte populations.

The above correlations continue as researchers examine chemokines expressed in samples from asthmatic patient populations. Chemokines previously identified in the airways of asthmatics include CCL5/RANTES, CCL11/eotaxin, MIP-1a/CCL3, CCL7/MCP-1, CCL13/MCP-4, CCL24/Eot-2, CCL17/TARC, CCL22/MDC, CCL28 and CxCL10. The importance of individual chemokines and chemokine receptors in allergic airway inflammation has been investigated using knockout mice sensitized and challenged with allergens including ovalbumin (OVA) and cockroach allergen (CRA) or with infectious challenges including Aspergillus fumigatus [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] . The preferential expression of these chemokines within the airways is believed to regulate recruitment and activation of a range of leukocyte subtypes including eosinophils and Th2 lymphocytes to the lungs. CD4 + T cells recruited to the lungs following allergen challenge secrete additional Th2 cytokines such as IL-4 and IL-13, and these cytokines are known to modulate chemokine expression in the lungs, resulting in elevated levels of CCL11, CCL13, CCL22, CCL1 and CCL17 via regulation of signal transducers and activators of transcription 6 (STAT6)-mediated transcription pathways [15, 37, 38] . The chemokine receptors expressed on lymphocytes skewed toward a Th2 phenotype correspond to the expression of ligands that have been implicated in the pathogenesis of allergic airway disease. Recent studies have begun to elucidate the role of individual chemokine receptors in directing Th2-type cell trafficking. Lloyd et al. determined that recruitment of these cells in the initial stages of an allergic response is dependent on expression of CCR3 ligands, but that repeated antigen stimulation results in the predominant use of CCR4 pathways possibly due to a progressive increase in recruitment of CCR4 + cells [39] . Studies utilizing neutralizing CCR3 antibody or CCR3 -/mice have demonstrated that there is a significant defect in not only eosinophil accumulation but also the induction of airway hyperreactivity that may be related to T cell accumulation [40, 41] . CCR4 has also been detected on the majority of Th2 cells found in endobronchial biopsies collected from asthmatic patients after allergen challenge, while < 30% of the cells co-expressed CCR8 [12] . CCR3 expression was detected only on eosinophils. In these patients, CCL17 and CCL22 expression was strongly up-regulated in the airway epithelial cells following allergen challenge further indicating a key role for CCR4 in mediating T cell trafficking to the airways. Although the authors were unable to detect elevated levels of the CCR8 ligand CCL1, CCL17 has been shown to induce migration of CCR8 transfectants in addition to CCR4. As indicated above, CCR8 is expressed predominantly on Th2 cells and a recent study in CCR8 -/mice showed that, while the development of a peripheral Th2 response was normal, the response to a localized allergen challenge in the lungs was altered [14] . Allergen-challenged CCR8 -/mice exhibited reduced levels of Th2 cytokines in the lungs possibly due to an inability to recruit Th2-type lymphocytes to the lungs. The resulting alterations in the immune environment also led to attenuation of eosinophil recruitment. Although the cytokines and eosinophil accumulation was altered in allergic airway responses, no alteration in airway physiology was observed. This latter observation has been confirmed in two independent studies in different CCR8 -/mice [42, 43] . Other studies have shown that CCR8 + CD4 + T cells are directly associated with IL-10 production and appear to be phenotypically similar to T regulatory cells [44, 45] . Thus, these cells may have a significant role in maintaining or skewing the immune response toward a Th2 environment. It is clear that T cells play a critical role in modulating the immune environment within the lungs, and strategies that exploit the role of chemokines in Th2 cell recruitment may prove extremely beneficial in the development of new treatments for asthma.

Other chemokine receptors have also been implicated in mediating Th2 lymphocyte accumulation in the lungs of mice. In addition to their presence on naïve lymphocytes, receptors, such as CxCR4, CxCR5, CCR6 and CCR7, have now been identified on T lymphocytes that are of memory/activated phenotype as well as skewed helper cell populations [46] [47] [48] [49] [50] [51] [52] . These receptors may therefore have a role in recruitment of lymphocytes to the airways of asthmatic patients and lead to exacerbation of disease. This notion can already be supported in the existing literature where targeting CxCR4 or CCR6 have had a beneficial effect within models of allergic airway responses. In the case of blocking CxCR4, studies show that there is a beneficial effect regardless of whether the receptor or ligand (CxCL12) is blocked [24, 53] . In contrast to the CxCR4 results, studies with CCR6 -/mice demonstrated an altered migration of CD4 + lymphocytes to the lung, suggesting that tissue-specific migration was altered [32, 54] . There may be multiple explanations for results from the CxCR4 and CCR6 studies including interruption of normal trafficking patterns of memory/activated lymphocytes to lymphoid organs or target tissue as well as reduced pulmonary recruitment and activation of eosinophils that express these receptors. Further studies with other homeostatic receptors indicate that CCR7 expression on T cells in both human and mouse studies is also important for development of asthmatic responses [55, 56] .

Chemokines influence the immune response at multiple levels. The presentation of foreign antigen to T cells is the initiating step of the adaptive immune response, and a number of leukocytes are effective antigen-presenting cells (APC). The dendritic cell (DC) is particularly indispensable in this regard, expressing high levels of MHC class II on its surface [57] . Thus, it is not surprising that work has been undertaken to identify chemokines that mediate the trafficking of these highly motile cells from the bone marrow to non-lymphoidal tissues and, following encounter with antigen, to regional lymph nodes. Although differential expression of chemokine receptors during their maturation has not been fully characterized, mature DC express detectable levels of CCR1, CCR2, CCR5 and CCR6, as well as CXCR1, CXCR2 and CXCR4, and the respective ligands for these receptors are effective chemoattractants [6, [58] [59] [60] . In particular, immature DC express CCR6, which is down-regulated during the maturation process as the DC migrates to the lymph node to participate in its APC function. Using CCR6-deficient mice, studies have demonstrated defects in DC positioning in the gut mucosa as well as defects in DTH responses centered on T lymphocyte accumulation [61] [62] [63] . Thus, CCR6 has the potential to participate in a vast range of immunological responses and, therefore, may not be segregated to only a homeostatic function. Recent data using CCR6 -/mice during allergen-induced airways disease demonstrated a defect in the accumulation of DC subsets in the lungs of challenged animals [54] . These latter data, which suggest that CCR6 is important for DC accumulation in the lungs during allergic responses, have been supported by previous studies. CCR6 is preferentially displayed on myeloid DC populations, and allergen challenge invokes an influx of circulating myeloid DC into the lung [64] . As CCL20 has been shown to be produced by airway epithelial cells [65, 66] , CCR6 might be required for localization of DC subsets to the airway, become activated, and acquire antigen for transport back to the draining lymph node. Furthermore, there may be specific defects in defined subsets of DC within the airway and/or decreased accumulation within the draining lymph nodes attributed to the CCR6 deficiency.

A number of chemokines have also been suggested to have a role in determining DC function. DC can produce a number of chemokines that may aid in preferentially recruiting specific T cell subsets to the DC for antigen activation. One of the first chemokines described to be produced, CCL22, which binds to CCR4, has been shown to have a role in allergen-induced airway disease [67] [68] [69] . Interestingly, stromal cell-derived factor-1 (SDF-1), which binds CXCR4 and selectively attracts naive T cells, is also an attractant for DC and may be an important mediator to attract these cells for antigen presentation [70] [71] [72] . The macrophage is probably the beststudied APC with respect to chemokines. Although they are highly phagocytic, they also express MHC class II and can participate in antigen presentation. A number of the CC chemokines (MCP 1-5, RANTES) were originally described as chemoat-tractants for monocytes/macrophages, and most CC chemokine receptors (with the notable exception of CCR3) are found on the surface of these cells. Thus, chemokines and their receptors likely play a crucial role in the recruitment and activation of APC, as well as in providing a source of chemokine for recruiting T cells for antigen presentation.

The causes of severe asthma exacerbations are poorly understood. While it is clear that environmental levels of allergen can play a role, it is unlikely that this is sole cause of exacerbated asthma. Clinical studies have shown that a decrease in the CD4:CD8 T cell ratio in the bronchoalveolar lavage (BAL) of asthmatic patients is correlated with increased asthma severity. In stable asthmatics the ratio of CD4:CD8 T cells is 3:1; however, this ratio decreases to 1:1 in patients experiencing acute asthma attacks. Additionally, in cases of asthma death the CD4:CD8 T cell ratio is reversed to 1:2-1:6. A possible explanation for the increased recruitment of CD8 + T cells to the BAL of exacerbated patients may be viral infection [73] [74] [75] . It has been reported in adults that 80% of asthma exacerbations, as characterized by a decrease in the peak expiratory flow rate, are associated with viral infection. There are a number of respiratory viruses that may play an important role in the exacerbation of the viral responses. The clinical data clearly indicate that one of the common features of most pulmonary viral infections is the early and intense production of chemokines [76] [77] [78] . The viruses that have been ascribed to producing chemokines upon infection of target cells include rhinovirus (RV), adenovirus, influenza virus, respiratory syncytial virus (RSV), as well as parainfluenza and SARS. The one characteristic that these viruses have is an often intense inflammatory response that initiates damage in the lungs of susceptible patients. Those most at risk usually have underlying pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), or are transplant recipients, premature infants, etc., and suffer the most severe disease from the initiation of the anti-viral inflammatory responses [79, 80] .

There are a number of chemokines that are initiated by respiratory viruses that appear to be commonly induced, including CCL2, CCL3, CCL5, CxCL8, CxCL9, and CxCL10. Although some of these chemokines are produced during Th2-type allergic responses, many of these have primarily been associated with Th1-type responses, such as those needed for anti-viral responses. A number of studies have identified production of chemokines after viral infection of isolated cell populations via PAMPs, which activate innate molecules such as Toll-like receptors [81] [82] [83] [84] . The early and intense up-regulation of these chemokines would normally play an important role in the anti-viral responses. However, during asthmatic responses the overproduction of these chemokines leads to increased leukocyte recruitment and exac-erbated disease. As indicated above, the overproduction of these virus-associated chemokines leads to the accumulation of CD8 T cells. The identification of chemokine receptors on CD8 T cells has not been thoroughly investigated. Recent data would indicate that CCR1 appears to be one of the receptors that mediate CD8 T cell recruitment ( [85] and unpublished data). Other studies have indicated that CCR2, CCR5, and CxCR3 may individually allow the accumulation of CD8 T cells to a site of viral infection [86] [87] [88] [89] . The overall effect of producing specific chemokines that are induced during viral responses may be to elicit certain T cell subsets during disease. Data from our laboratory using RSV infection has shown that CCR1 specifically regulates CD8 T cells that produce Th2-type cytokines, especially IL-13 (unpublished data). This effect would bias the entire pulmonary immune environment toward ineffective clearance of the viral response and lead to enhanced Th2-mediated asthmatic reactions, especially mucus hypersecretion, as illustrated in Figure 1 . This mechanism may also operative in other diseases such as COPD, where mucus overproduction is related directly to the intensity of the CD8 + 122 Nicholas W. Lukacs and Matthew Schaller T cell recruitment [90] [91] [92] . In contrast, other recent publications have identified an important role for CxCR3 for the recruitment of cytotoxic CD8 + T cells for clearance of MHV-68 during lung infection [93, 94] . While this subset may be important with clearance of virus, it was also associated with development of chronic cough in non-asthmatic children [95] and may be associate with post-viral syndromes. Thus, there may be a preferential use of chemokine receptors during viral responses that dictate the phenotype of the CD8 + T cell that is recruited to the airways.

Although a number of chemokine receptors that have been described that mediate the accumulation of T lymphocytes to the lung during disease progression, there 123 Lymphocyte trafficking and chemokine receptors during pulmonary disease continues to be a paucity of data regarding their specific function during certain pulmonary diseases. Questions persist on whether the differential receptor display on T cell subsets described in in vitro experiments, represent those that cause accumulation during disease. The diversity of chemokine production and the promiscuous pattern of chemokine-chemokine receptor interactions have made the identification of individual chemokine or chemokine receptor targets for therapeutic intervention extremely difficult. Interestingly, several of the "lead" candidates for targeting during chronic asthmatic disease are receptors that appear to bind a single or at most two chemokines, including CxCR4, CCR4, CCR6, and CCR8 (Table 2) . Choosing the proper targets for specific disease phenotypes will only occur after careful coordinated animal modeling experiments coupled with translational research efforts in human disease. 

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