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Eosinophils: Singularly destructive effector cells or purveyors of immunoregulation?

2007; Elsevier BV; Volume: 119; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2007.03.043

1097-6825

Elizabeth A. Jacobsen, Anna G. Taranova, Nancy A. Lee, James J. Lee,

Eosinophilic Esophagitis

Eosinophils are granulocytes typically associated with immune responses to a limited number of specific insults, including helminth infection and exposure to various allergens. Moreover, the overwhelming consensus from the literature is that eosinophils evolved as uniquely destructive leukocytes with cytotoxic activities as an adaptation for host defense. However, recent studies now suggest that the parochial caricature of eosinophils as effector cells with nonspecific killing abilities that evolved as a host defense mechanism against large nonphagotizable parasites is incomplete. A new paradigm has emerged describing eosinophils as initial responders to cell death/tissue damage that are a part of remodeling/repair processes and, more importantly, significant contributors to localized innate and acquired immune responses as well as systemic adaptive immunity. Significantly, this new paradigm does not preclude roles for eosinophils in host defense leading to tissue damage but instead suggests the equal importance of eosinophil-associated regulatory mechanisms modulating local tissue immune responses. The goal of this review is to summarize the data in support of this new paradigm. In turn, we believe that this expanded role provides a probable explanation for the presence of eosinophils in diverse disease settings such as asthma, allergy, cancer, transplant rejection, gastrointestinal inflammation, and viral or helminth infection. Eosinophils are granulocytes typically associated with immune responses to a limited number of specific insults, including helminth infection and exposure to various allergens. Moreover, the overwhelming consensus from the literature is that eosinophils evolved as uniquely destructive leukocytes with cytotoxic activities as an adaptation for host defense. However, recent studies now suggest that the parochial caricature of eosinophils as effector cells with nonspecific killing abilities that evolved as a host defense mechanism against large nonphagotizable parasites is incomplete. A new paradigm has emerged describing eosinophils as initial responders to cell death/tissue damage that are a part of remodeling/repair processes and, more importantly, significant contributors to localized innate and acquired immune responses as well as systemic adaptive immunity. Significantly, this new paradigm does not preclude roles for eosinophils in host defense leading to tissue damage but instead suggests the equal importance of eosinophil-associated regulatory mechanisms modulating local tissue immune responses. The goal of this review is to summarize the data in support of this new paradigm. In turn, we believe that this expanded role provides a probable explanation for the presence of eosinophils in diverse disease settings such as asthma, allergy, cancer, transplant rejection, gastrointestinal inflammation, and viral or helminth infection. Eosinophils are a changing paradigm. The classic view of eosinophils as singularly destructive effector cells responsible for host defense against select pathogens (eg, helminths) and the pathologies associated with allergic diseases such as asthma has been a dogmatic perspective that has changed very little since the first identification of the eosinophil.1Rothenberg M.E. Hogan S.P. The eosinophil.Annu Rev Immunol. 2006; 24: 147-174Crossref PubMed Scopus (1278) Google Scholar This classic view further suggests that eosinophil effector functions are activities that derive almost exclusively as a consequence of releasing the toxic cationic proteins (eosinophil specific granule proteins; ESGPs) stored in the secondary granules of these leukocytes (see review2Gleich G.J. Loegering D.A. Immunobiology of eosinophils.Annu Rev Immunol. 1984; 2: 429-459Crossref PubMed Scopus (154) Google Scholar). We suggest that this view arose because of 3 independent events: (1) the unique association of large numbers of an otherwise rare cell type with helminth infections and allergic diseases such as asthma; (2) the enigmatic presence of eosinophils in areas of tissue damage, including the granulomous areas surrounding parasites, and sites of inflammation in the lungs of patients with asthma; and (3) the toxic cationic character of the ESGPs together with their lack of defined effector functions either because of the absence of enzymatic activity (ie, major basic protein [MBP]–1 and MBP-2) or enzymatic activities not easily integrated into existing hypotheses of effector function other than as toxic mediators (ie, eosinophil peroxidase [EPO] and the eosinophil-associated ribonucleases eosinophil cationic protein [ECP] and eosinophil-derived neurotoxin [EDN]). However, the last decade bears witness to a remarkable shift in this perspective, primarily driven by the ambiguous character and failure of several studies demonstrating that eosinophils are essential to immune responses leading to parasite death and/or elimination from the host or that eosinophils are the primary cause of the pulmonary inflammation and pathology associated with patients with asthma. Moreover, reports in the literature demonstrate that the presence of eosinophils is common in a myriad of circumstances independent of both parasite infection and allergy (eg, eosinophils are a prominent infiltrate of most cancers and a recruited cell type in response to some viral infections). In other circumstances, an observed tissue eosinophilia appears to be part of baseline homeostatic mechanisms, occurring in the absence of disease pathology (eg, the resident tissue eosinophilia of the gastrointestinal areas and reproductive tract, as well as the baseline eosinophilia associated with the thymus). This review highlights evidence of an emerging paradigm from recent studies suggesting that the primary function of eosinophils appears to be tissue remodeling, repair, and, more importantly, immunoregulation. Specifically, we review a growing body of literature demonstrating that tissue-infiltrating eosinophils are essential components of the local immune microenvironment, exchanging signals with virtually every resident cell of a given tissue, including autocrine activities on eosinophils themselves that promote localized accumulation/activation (Fig 1). In particular, eosinophils appear to modulate acute phase and innate inflammatory responses as well as acquired immunity associated with both TH1 and TH2 immune responses. Interestingly, eosinophils also have activities linked to immune suppression that potentially modulate T-regulatory cell function and thymocyte development, suggesting that in a given tissue and/or immune response, eosinophils potentially play either proinflammatory or anti-inflammatory roles. Thus, instead of destructive effector cells whose presence clinically in a vast array of diseases (eg, asthma, allergy, cancer, transplant rejection, gastrointestinal inflammation, and viral or helminth infection) is almost universally viewed as causative of host cell death and tissue damage, eosinophils are more appropriately viewed as essential components of homeostasis whose presence in disease is a prognostic indicator of pathology. One of the interesting, and perhaps more important, means by which eosinophils modulate the immune microenvironment are cell autonomous mechanisms that promote the recruitment and local survival of eosinophils themselves. Specifically, eosinophils express an array of cell surface receptors that are critical to their own survival, recruitment, and activation, including cytokine receptors (eg, IL-5 receptor [IL-5R], IL-4R, IL-13R, GM-CSFR, c-kit), chemokine receptors (eg, CCR3), complement receptors, immunoglobulin receptors (eg, FcɛRII), leukotriene receptors, and receptors for growth factors (eg, TGF-β receptor).3Tachimoto H. Bochner B.S. The surface phenotype of human eosinophils.Chem Immunol. 2000; 76: 45-62Crossref PubMed Scopus (55) Google Scholar More importantly, eosinophils are also robust sources of the ligands that bind these receptors, suggesting the existence of local autocrine and paracrine regulatory loops by which eosinophils in part control both their local tissue accumulation and effector functions. Studies of Schistosoma mansoni infection provide representative examples in which eosinophil-dependent autoregulation of TH2 cytokines (eg, IL-4 and IL-5) appears to be an essential component of host immune responses.4Sabin E.A. Kopf M.A. Pearce E.J. Schistosoma mansoni egg-induced early IL-4 production is dependent upon IL-5 and eosinophils.J Exp Med. 1996; 184: 1871-1878Crossref PubMed Scopus (179) Google Scholar, 5Swartz J.M. Dyer K.D. Cheever A.W. Ramalingam T. Pesnicak L. Domachowske J.B. et al.Schistosoma mansoni infection in eosinophil lineage-ablated mice.Blood. 2006; 108: 2420-2427Crossref PubMed Scopus (167) Google Scholar Although under many circumstances eosinophils clearly depend on T cells for their initial recruitment to sites of inflammation, eosinophils themselves may propagate the immune response through recruitment of T-effector/memory cells. Eosinophils potentially promote chemoattraction of TH1 cells through the expression of chemokines that bind CXCR3 on T cells (eg, CXCL10 [IP10] and CCR3 [RANTES]).6Gutierrez-Ramos J.C. Lloyd C. Kapsenberg M.L. Gonzalo J.A. Coyle A.J. Non-redundant functional groups of chemokines operate in a coordinate manner during the inflammatory response in the lung.Immunol Rev. 2000; 177: 31-42Crossref PubMed Scopus (75) Google Scholar In addition, the presence of eosinophils in draining lymph nodes after allergen provocation7MacKenzie J.R. Mattes J. Dent L.A. Foster P.S. Eosinophils promote allergic disease of the lung by regulating CD4+ Th2 lymphocyte function.J Immunol. 2001; 167: 3146-3155Crossref PubMed Scopus (191) Google Scholar, 8Duez C. Dakhama A. Tomkinson A. Marquillies P. Balhorn A. Tonnel A.-B. et al.Migration and accumulation of eosinophils toward regional lymph nodes after airway allergen challenge.J Allergy Clin Immunol. 2004; 114: 820-825Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar suggests that eosinophil-derived chemokines may even promote T-cell recruitment to lymph nodes as part of a mechanism leading to T-cell activation and the generation of antigen-specific memory-effector cells. Alternatively, eosinophils and other granulocytes may promote T-cell recruitment as part of TH2-driven inflammatory responses through the release of inflammatory lipid mediators such as leukotrienes (eg, leukotriene B49Miyahara N. Takeda K. Miyahara S. Taube C. Joetham A. Koya T. et al.Leukotriene B4 receptor-1 is essential for allergen-mediated recruitment of CD8+ T cells and airway hyperresponsiveness.J Immunol. 2005; 174: 4979-4984Crossref PubMed Scopus (105) Google Scholar). Finally, although these discussions focused on direct mechanisms by which eosinophils may promote T-cell chemotaxis, indirect mechanisms leading to T-cell recruitment, such as eosinophil-mediated activation of resident third party cells in the lung (eg, airway epithelium), are likely to be significant as well. Parasite infections and atopic diseases including asthma are characterized by TH2/Tc2 immune responses that lead to the elaboration of the representative cytokines IL-4, IL-5, IL-9, and IL-13.10Lamkhioued B. Gounni A.S. Aldebert D. Delaporte E. Prin L. Capron A. et al.Synthesis of type 1 (IFN gamma) and type 2 (IL-4, IL-5, and IL-10) cytokines by human eosinophils.Ann N Y Acad Sci. 1996; 796: 203-208Crossref PubMed Scopus (84) Google Scholar These immune responses collectively result from the activities of multiple T-cell subtypes, including CD4+ TH memory-effector cells, natural killer T cells, and CD8+ T cells that have been polarized to express TH2 cytokines. However, the ubiquitous presence of eosinophils at sites of TH2-mediated inflammation and their demonstrated abilities to express each of the representative TH2 cytokines have led to speculation that eosinophils themselves are capable of modulating and/or sustaining the TH2 character of the local tissue immune microenvironment.11Schmid-Grendelmeier P. Altznauer F. Fischer B. Bizer C. Straumann A. Menz G. et al.Eosinophils express functional IL-13 in eosinophilic inflammatory diseases.J Immunol. 2002; 169: 1021-1027Crossref PubMed Scopus (209) Google Scholar In addition, in situ hybridization assessments of gene expression,12Justice J.P. Borchers M.T. Lee J.J. Rowan W.H. Shibata Y. Van Scott M.R. Ragweed-induced expression of GATA-3, IL-4, and IL-5 by eosinophils in the lungs of allergic C57BL/6J mice.Am J Physiol Lung Cell Mol Physiol. 2002; 282: L302-L309Crossref PubMed Scopus (27) Google Scholar, 13Gessner A. Mohrs K. Mohrs M. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production.J Immunol. 2005; 174: 1063-1072Crossref PubMed Scopus (236) Google Scholar studies using IL-4 gene reporter strategies,14Chen L. Grabowski K.A. Xin J.P. Coleman J. Huang Z. Espiritu B. et al.IL-4 induces differentiation and expansion of Th2 cytokine-producing eosinophils.J Immunol. 2004; 172: 2059-2066Crossref PubMed Scopus (84) Google Scholar and adoptive transfer of IL-13–deficient T cells15Voehringer D. Reese T.A. Huang X. Shinkai K. Locksley R.M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system.J Exp Med. 2006; 203: 1435-1446Crossref PubMed Scopus (279) Google Scholar have shown that eosinophils infiltrating sites of TH2 inflammation express IL-4/IL-13, suggesting these granulocytes may represent significant local sources of IL-4/IL-13 that occur at the sites of TH2-mediated inflammation. Indeed, mice that are deficient of eosinophils appear to have both impaired T-cell recruitment (unpublished observations) and reduced TH2 cytokine production in the lungs of allergen-challenged mice.16Lee J.J. Dimina D. Macias M.P. Ochkur S.I. McGarry M.P. O'Neill K.R. et al.Defining a link with asthma in mice congenitally deficient in eosinophils.Science. 2004; 305: 1773-1776Crossref PubMed Scopus (645) Google Scholar, 17Fulkerson P.C. Fischetti C.A. McBride M.L. Hassman L.M. Hogan S.P. Rothenberg M.E. A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation.Proc Natl Acad Sci U S A. 2006; 103: 16418-16423Crossref PubMed Scopus (191) Google Scholar The importance of the ability of eosinophils to modulate TH2 immune responses is not limited to parasite infection and allergy and may play significant roles in other disease states such as the immune responses associated with transplant rejection, chronic inflammatory diseases, and cancer. Furthermore, in many of these diseases, the ability of eosinophils to modulate immune responses appears to have important downstream consequences for local tissue remodeling/repair.18Fulkerson P.C. Rothenberg M.E. Hogan S.P. Building a better mouse model: experimental models of chronic asthma.Clin Exp Allergy. 2005; 35: 1251-1253Crossref PubMed Scopus (32) Google Scholar For example, IL-4–deficient mice have reduced transplant-associated eosinophilia and impaired TH2 inflammation at the site of incompatible allograft transplants, suggesting that eosinophils may modulate the immune responses leading to transplant rejection.19Surquin M. Le Moine A. Flamand V. Nagy N. Rombaut K. Demoor F.X. et al.Skin graft rejection elicited by beta 2-microglobulin as a minor transplantation antigen involves multiple effector pathways: role of Fas-Fas ligand interactions and Th2-dependent graft eosinophil infiltrates.J Immunol. 2002; 169: 500-506Crossref PubMed Scopus (21) Google Scholar In addition, both IL-4 and IL-13 are associated with tumor cell death in many types of cancer,20Debinski W. Obiri N.I. Pastan I. Puri R.K. A novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin is highly cytotoxic to human carcinoma cells expressing receptors for interleukin 13 and interleukin 4.J Biol Chem. 1995; 270: 16775-16780Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar and our recent studies using eosinophil-specific antibodies have demonstrated that nearly all human and/or mouse cancers are associated with a robust eosinophil infiltrate at some point in tumor growth.21Cormier S.A. Taranova A.G. Bedient C. Nguyen T. Protheroe C. Pero R. et al.Pivotal advance: eosinophil infiltration of solid tumors is an early and persistent inflammatory host response.J Leukoc Biol. 2006; 79: 1131-1139Crossref PubMed Scopus (151) Google Scholar Thus, although further analyses are certainly needed, it is interesting to speculate that eosinophils may be a little recognized participant in the modulation of tumor-associated TH2 immune responses (or alternatively the downregulation of tumor-associated cytotoxic TH1 responses). Although the literature abounds with studies suggesting that eosinophils are intimately linked with TH2-driven immunity, these granulocytes have also been demonstrated to express many of the hallmark cytokines that characterize TH1 immune responses. Specifically, eosinophils have been shown to express IL-12 and IFN-γ.10Lamkhioued B. Gounni A.S. Aldebert D. Delaporte E. Prin L. Capron A. et al.Synthesis of type 1 (IFN gamma) and type 2 (IL-4, IL-5, and IL-10) cytokines by human eosinophils.Ann N Y Acad Sci. 1996; 796: 203-208Crossref PubMed Scopus (84) Google Scholar Eosinophils have also been shown to express several Toll-like receptors (eg, Toll-like receptor 722Nagase H. Okugawa S. Ota Y. Yamaguchi M. Tomizawa H. Matsushima K. et al.Expression and function of Toll-like receptors in eosinophils: activation by Toll-like receptor 7 ligand.J Immunol. 2003; 171: 3977-3982Crossref PubMed Scopus (263) Google Scholar), which are part of innate immune responses that generally lead to TH1 acquired immune responses. Furthermore, eosinophil expression of IL-12 receptor implies that tissue infiltrating eosinophils are capable of recognizing and responding to a localized TH1 immune microenvironment, suggesting that some specific eosinophil activities/responses may occur as a consequence of the balance between TH1-TH2 immune responses in a given tissue. Eosinophils are generally not associated with acute phase inflammatory responses; however, a review of the literature shows that their presence is often noted. In particular, noted examples include wound healing, rheumatoid arthritis, cancer, and nonallergic gastrointestinal disorders (eg, inflammatory bowel disease). Significantly, eosinophils have been shown to both express and respond to each of the cytokines typically associated with acute phase inflammatory responses (ie, TNF-α, IL-1, IL-6, IL-8). For example, eosinophil-dependent mechanisms of TNF-α function have been implicated in paracrine and autocrine mechanisms of inflammation (asthma and ulcerative colitis).23Lampinen M. Carlson M. Hakansson L.D. Venge P. Cytokine-regulated accumulation of eosinophils in inflammatory disease.Allergy. 2004; 59: 793-805Crossref PubMed Scopus (277) Google Scholar The production of TNF-α by eosinophils localized to tumors may also play a significant role in some cancers that depend heavily on vascular angiogenesis (eg, colon, breast, and melanoma).24Puxeddu I. Ribatti D. Crivellato E. Levi-Schaffer F. Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases.J Allergy Clin Immunol. 2005; 116: 531-536Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar These studies suggest eosinophils have a direct ability to modulate resident cells in tissues/organs (eg, endothelial adhesion, epithelial activation, fibroblast activation) and enhance the responses of other leukocytes (eg, neutrophils and macrophages). In addition to defined roles in inflammatory responses, there is growing evidence that eosinophils may dampen local inflammatory responses by either modulating the activities of T regulatory cells or specifically altering the local character of the TH2/TH1 responses occurring in the immune microenvironment. Specifically, the demonstrated ability of eosinophils to express IL-10, TGF-β, and indoleamine 2,3,-dioxygenase broadens the potential roles of eosinophils beyond the classic view of a proinflammatory effector cell. For example, the demonstration that eosinophils express IL-1010Lamkhioued B. Gounni A.S. Aldebert D. Delaporte E. Prin L. Capron A. et al.Synthesis of type 1 (IFN gamma) and type 2 (IL-4, IL-5, and IL-10) cytokines by human eosinophils.Ann N Y Acad Sci. 1996; 796: 203-208Crossref PubMed Scopus (84) Google Scholar and are a particularly robust source of TGF-β25Ohno I. Nitta Y. Yamauchi K. Hoshi H. Honma M. Woolley K. et al.Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation.Am J Respir Cell Mol Biol. 1996; 15: 404-409Crossref PubMed Scopus (251) Google Scholar suggests that the tissue-specific accumulation of eosinophils may modulate local T-regulatory cell activities. Alternatively, eosinophil expression of IL-10 and/or TGF-β may also prevent the polarization of naive (TH0) lymphocytes to either the TH1 or TH2 phenotype and the associated expression of IL-2 leading to the expansion of these T-cell populations. In addition to activities that may potentially modulate T-regulatory cell development, eosinophils may promote TH1/TH2 imbalance through expression of indoleamine 2,3,-dioxygenase,26Odemuyiwa S.O. Ghahary A. Li Y. Puttagunta L. Lee J.E. Musat-Marcu S. et al.Cutting edge: human eosinophils regulate T cell subset selection through indoleamine 2,3-dioxygenase.J Immunol. 2004; 173: 5909-5913Crossref PubMed Scopus (179) Google Scholar which catabolized in situ local tryptophan, thus lowering the viability or activation of T cells. In either case, each of these activities in turn potentially contributes to the suppression of inflammatory events within the tissue microenvironment, suggesting a previously underappreciated role for eosinophils as a potential negative regulator of local inflammation. Antigen presentation to T cells has long been recognized as a critical event leading to allergen-specific acquired immunity (ie, the generation of memory-effector cells and T-cell proliferation). Although generally thought of as a process mediated by professional antigen-presenting cells (APCs) such as dendritic cells, B lymphocytes, and macrophages, several studies over the past 15 years have implicated eosinophils as functional APCs. Specifically, eosinophils have been shown to induce antigen-specific MHC II–restricted T-cell proliferation in vitro, although not at levels equivalent to macrophage activity.27Del Pozo V. De Andres B. Martin E. Cardaba B. Fernandez J.C. Gallardo S. et al.Eosinophil as antigen-presenting cell: activation of T cell clones and T cell hybridoma by eosinophils after antigen processing.Eur J Immunol. 1992; 22: 1919-1925Crossref PubMed Scopus (112) Google Scholar Moreover, in a series of elegant eosinophil adoptive transfer studies, these results were extended in vivo by using mouse models of allergen provocation, showing that eosinophils express on their cell surfaces not only MHC II but also many of the costimulatory ligands (eg, CD80 and CD86) generally associated with antigen presentation and T-cell activation.28Shi H.-Z. Xiao C.-Q. Li C.-Q. Mo X.-Y. Yang Q.-L. Leng J. et al.Endobronchial eosinophils preferentially stimulate T helper cell type 2 responses.Allergy. 2004; 59: 428-435Crossref PubMed Scopus (44) Google Scholar In addition, these studies (later confirmed by other investigators7MacKenzie J.R. Mattes J. Dent L.A. Foster P.S. Eosinophils promote allergic disease of the lung by regulating CD4+ Th2 lymphocyte function.J Immunol. 2001; 167: 3146-3155Crossref PubMed Scopus (191) Google Scholar, 8Duez C. Dakhama A. Tomkinson A. Marquillies P. Balhorn A. Tonnel A.-B. et al.Migration and accumulation of eosinophils toward regional lymph nodes after airway allergen challenge.J Allergy Clin Immunol. 2004; 114: 820-825Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar) showed that eosinophils had the ability to traffic to draining paratracheal lymph nodes of the lung and stimulate antigen-specific CD4+ T cells. Unfortunately, the provocative character of these observations is not without controversy, because issues have arisen about the specific character of the antigen-presenting ability of eosinophils. Specifically, adoptive transfer studies by van Rijt et al29van Rijt L.S. Vos N. Hijdra D. de Vries V.C. Hoogsteden H.C. Lambrecht B.N. Airway eosinophils accumulate in the mediastinal lymph nodes but lack antigen-presenting potential for naive T cells.J Immunol. 2003; 171: 3372-3378Crossref PubMed Scopus (76) Google Scholar questioned the characterization of eosinophils as professional APCs, showing in an allergen challenge model of asthma that dendritic cells rather than eosinophils were responsible for inducing proliferation and activation of naive T cells from peribronchial lymph nodes. However, these authors showed that eosinophils appeared capable of stimulating ovalbumin-specific memory-effector T cells, and it has also been suggested recently that the discrepancy between reports in the current literature may result from differences in the eosinophil isolation methods used (P. Weller, personal communication, January 2007). Interestingly, a recent series of studies using a mouse model of Strongyloides stercoralis infection appeared to confirm the ability of eosinophils to present antigen even to naive T cells30Padigel U.M. Lee J.J. Nolan T.J. Schad G.A. Abraham D. Eosinophils can function as antigen-presenting cells to induce primary and secondary immune responses to Strongyloides stercoralis.Infect Immun. 2006; 74: 3232-3238Crossref PubMed Scopus (142) Google Scholar (D. Abraham, personal communication, January 2007). Specifically, adaptive immune responses to S stercoralis were dependent on MHC II expression by eosinophils and in these studies eosinophils were shown to be more effective at inducing TH2 responses than dendritic cells. Thus, we would argue the available data show that eosinophils are capable of presenting antigen, they function in this capacity under physiologically relevant conditions, and in some cases this ability may be critical to the development of acquired immune responses. In other words, discussions about whether eosinophils present antigens efficiently are inconsequential. APCs are defined so because they perform that function in vivo, not because they are necessarily good at it. T-cell development, proliferation, and selection are conducted within distinct regions of the thymus: entry into the thymus at the cortico-medullary border, positive selection via epithelial cells in the cortical region, and negative selection via dendritic cells and other antigen-presenting myeloid cells in the medullary region before departure from the thymus. Historically, the presence of eosinophils in the thymus has been a well characterized observation,31Muller E. Localization of eosinophils in the thymus by the peroxidase reaction.Histochemistry. 1977; 52: 273-279Crossref PubMed Scopus (24) Google Scholar yet the significance of this thymic eosinophilia remains unknown. Nonetheless, recent studies have suggested that eosinophils may modulate T-cell activities indirectly by participating in thymocyte education (ie, T-cell selection). This hypothesis is fueled by several observations. First, thymic eosinophil numbers reach a maximum at 2 weeks of age in mice32Throsby M. Herbelin A. Pleau J.M. Dardenne M. CD11c+ eosinophils in the murine thymus: developmental regulation and recruitment upon MHC class I-restricted thymocyte deletion.J Immunol. 2000; 165: 1965-1975Crossref PubMed Scopus (104) Google Scholar and 2 to 3 years in human beings,33Lee I. Yu E. Good R.A. Ikehara S. Presence of eosinophilic precursors in the human thymus: evidence for intra-thymic differentiation of cells in eosinophilic lineage.Pathol Int. 1995; 45: 655-662Crossref PubMed Scopus (17) Google Scholar with declining numbers within 16 weeks and adulthood, respectively. In both mammals, thymic eosinophil numbers parallel the kinetics of T-cell production and release from the thymus. Second, the localization of eosinophils within the thymus in both mouse and human beings also suggests a role in T-cell selection. Eosinophils are found predominantly in the cortico-medullary junction before birth and migrate to the medulla at approximately the same time as the maxima of T-cell production and release (E. Jacobsen, our unpublished data, January 2007). Third, Throsby et al,32Throsby M. Herbelin A. Pleau J.M. Dardenne M. CD11c+ eosinophils in the murine thymus: developmental regulation and recruitment upon MHC class I-restricted thymocyte deletion.J Immunol. 2000; 165: 1965-1975Crossref PubMed Scopus (104) Google Scholar using MHC I–restricted H-Y T-cell receptor transgenic mice, demonstrated a temporal and spatial association between thymic eosinophils and class I–restricted negative selection in the thymus after administration of a cognate H-Y peptide. Collectively, each of the observations suggests that thymic eosinophils have the novel role of regulating immune responses at homeostatic baseline through effects on T-cell selection. An interesting variation on the theme of eosinophils as professional APCs are observations that eosinophil may facilitate antigen presentation by augmenting the ability of other APCs. For example, Yang et al34Yang D. Rosenberg H.F. Chen Q. Dyer K.D. Kurosaka K. Oppenheim J.J. Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells.Blood. 2003; 102: 3396-3403Crossref PubMed Scopus (137) Google Scholar demonstrated that the eosinophil-associated ribonuclease EDN induced se