Th1/Th2 lymphocytes: Doubt some more☆☆☆★
1997; Elsevier BV; Volume: 99; Issue: 2 Linguagem: Inglês
10.1016/s0091-6749(97)70090-3
ISSN1097-6825
Autores Tópico(s)IL-33, ST2, and ILC Pathways
ResumoThe concept of T helper lymphocyte heterogeneity with Th 1 and Th 2 subclasses, which can be distinguished on the basis of their cytokine repertoire, has been a useful paradigm in studies on the immunology of allergic disorders.1Mosmann TR Coffman RL. Two types of mouse helper T-cell clone: implications for immune regulation.Immunol Today. 1987; 8: 223-226Abstract Full Text PDF Scopus (469) Google Scholar Th 1 cells are generally defined by their synthesis of IL-2, interferon (IFN)-γ, and tumor necrosis factor-β and are involved in cellular immunity; whereas Th 2 cells are reported to produce IL-4, IL-5, IL-9, IL-10, and IL-13 and are involved in humoral immune responses and allergy. This paradigm has led to the concept that T helper lymphocyte responses to allergens are Th 2-like in allergic subjects and Th 1-like in nonallergic subjects, and as such, immunotherapy should work by converting Th 2 into Th 1 responses. Although appealing in its simplicity, the true nature of cytokine responses to antigens is much more complex than can be explained by this Th 1/Th 2 dichotomy. In most immune responses, T cells do not develop distinct Th 1/Th 2 cytokine profiles, but rather many different cytokine combinations. Restricted cytokine profiles are primarily observed after the generation of antigen-specific clones but are implied by in vivo and ex vivo pathology. However, cloning is an artifactual process, and the result does not necessarily reflect the physiologic response to the antigen. The repeated pulse stimulation with antigen, the physical chemical nature and dose of the antigen, the choice of antigen-presenting cell, the requirement for cytokine growth factors to maintain T-cell viability, and many other variables will all influence T helper differentiation. There are additional caveats concerning this differentiation in vitro of Th 1/Th 2 lymphocytes. No firm differentiation markers exist that distinguish a Th 1 from a Th 2 cell, and these subgroups may not represent distinct subpopulations. The situation in human beings is additionally confused by significant limitations concerning the clear distinction between the cytokine profiles of Th 1 and Th 2 cells. In human beings, both subsets may make IL-2, IL-10, and IL-13 in addi-tion to their shared production of granulocyte-macrophage colony-stimulating factor and IL-3. Despite these concerns, a role for Th 2-like cells in the pathophysiology of allergic disorders is convincingly demonstrated by numerous observations. The presence in vivo of malignant, functionally active Th 2 lymphocyte clones in patients with Sézary syndrome or other lymphoproliferative disorders has been associated with elevated IgE and eosinophilia.2Borish L Dishuck J Cox L Mascali JJ Williams J Rosenwasser LJ Sézary syndrome with elevated serum IgE and hypereosinophilia: role of dysregulated cytokine production.J Allergy Clin Immunol. 1993; 92: 123-131Abstract Full Text PDF PubMed Scopus (32) Google Scholar, 3Cogan E Schandene L Crusiaux A Cochaux P Velu T Goldman M Clonal proliferation of type 2 helper T cells in a man with the hypereosinophil syndrome.N Engl J Med. 1994; 330: 535-538Crossref PubMed Scopus (280) Google Scholar Bronchial biopsy specimens from patients with allergic asthma4Robinson DS Hamid Q Ying S Tsicopoulos A Barkans J Bentley J et al.Predominant T H 2-like bronchoalveolar T-lymphocyte population in atopic asthma.N Engl J Med. 1992; 326: 298-304Crossref PubMed Scopus (2541) Google Scholar and skin test challenge sites from atopic patients5Gaglani B Borish L Buchmeier A Keller L Nelson H. Local nasal immunotherapy (LNIT) with aqueous weed extract is an effective therapy for weed induced rhinitis.J Allergy Clin Immunol. 1996; 97 ([abstract]): 301Abstract Full Text PDF Google Scholar are characterized by T helper lymphocytes displaying a Th 2-like cytokine profile. However, although there may be a reduced presence of the Th 1 cytokines, allergic d isorders are also characterized by the presence of IFN-γ. IFN-γ can readily be identified both as transcripts and protein in bronchoalveolar lavage fluid and biopsy specimens4Robinson DS Hamid Q Ying S Tsicopoulos A Barkans J Bentley J et al.Predominant T H 2-like bronchoalveolar T-lymphocyte population in atopic asthma.N Engl J Med. 1992; 326: 298-304Crossref PubMed Scopus (2541) Google Scholar (D. Broide. Personal communication), in nasal lavage fluid in which it may be one of the more prevalent cytokines,5Gaglani B Borish L Buchmeier A Keller L Nelson H. Local nasal immunotherapy (LNIT) with aqueous weed extract is an effective therapy for weed induced rhinitis.J Allergy Clin Immunol. 1996; 97 ([abstract]): 301Abstract Full Text PDF Google Scholar and in the supernatant of allergen-specific T helper lymphocyte cell lines.6Slunt JB Taketomi EA Woodfolk JA Platts-Mills TAE Distinct cytokine profiles among subjects with immediate and delayed hypersensitivity to Trichophyton tonsurans [abstract].J Allergy Clin Immunol. 1996; 97: 408Abstract Full Text PDF Google Scholar, 7Ikagawa S Matsushita S Chen Y-Z Ishikawa T Nishimura Y. Single amino acid substitutions on a Japanese cedar pollen allergen (Cry j 1)-derived peptide induced alterations in human T cell responses and T cell receptor antagonism.J Allergy Clin Immunol. 1996; 97: 53-64Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Through its ability to activate accessory cell function, stimulate IL-1, tumor necrosis factor-α, and IL-6 release, induce endothelial cell adhesion molecule expression, and support the recruitment and activation of inflammatory cells, it is likely that IFN-γ is a proinflammatory cytokine that exacerbates the severity of allergic inflammation. The pattern of cytokine response to allergens observed in nonallergic individuals is even more complex. Normal individuals are exposed to the same concentrations of allergens as patients with allergy living in the same environment. Remaining healthy requires active systems, which prevent the development of inflammation. It is frequently stated that the immune response to allergens in nonallergic subjects is characterized by Th 1-like lymphocyte responses.8Wierengara EA Snoek M de Groot C Chretien I Bos JD Jansen M et al.Evidence for compartmentalization of functional subsets of CD4+ T lymphocytes in atopic patients.J Immunol. 1990; 144: 4651-4656PubMed Google Scholar, 9Sallusto F Quintieri F Pugliese O Reale G Pini C Di Felice G T-cell and antibody response to Parietaria judaica allergenic fractions in atopic and nonatopic individuals.Allergy. 1993; 48: 37-44Crossref PubMed Scopus (18) Google Scholar, 10Imada M Simons FER Jay FT Hayglass KT Allergen-stimulated interleukin-4 and interferon-γ production in primary culture: response of subjects with allergic rhinitis and normal controls.Immunology. 1995; 85: 373-380PubMed Google Scholar Numerous published observations support this hypothesis, including the generation of allergen-specific Th 1-like clones from nonallergic subjects, which secrete IFN-γ but not IL-4 or IL-5. However, functional Th 1 responses will also stimulate the recruitment and activation of mononuclear phagocytes. Th 1-like lymphocytes are readily identified in the cellular immune responses to purified protein derivative and other immune responses characterized by cellular immunity and granuloma formation. However, the normal state is not characterized by delayed-type hypersensitivity–like cellular inflammatory responses to allergens. Normal subjects remain healthy because they are able to inhale allergens without experiencing inflammation. Therefore the demonstration of Th 1 responses either represents an in vitro artifact of the cloning process or, if present in vivo, must be present in a milieu that actively prevents cellular inflammation from developing. In vitro studies that remove T helper lymphocytes from their natural surroundings may artificially promote the differentiation of Th 1-like cells. For example, the use of activated antigen-presenting cells, biologically implausible concentrations of the allergens, or adjuvants such as contaminating endotoxin in the culture media or allergen extract may all permit the in vitro differentiation of Th 1 cells. The absence of inflammation in normal subjects is primarily maintained by influences that promote the development of tolerance. Immune responses to allergens may develop in nonatopic subjects, but despite identical antigen doses, these responses are generally of a lower order of magnitude than those observed in allergic subjects. Thus nonallergic subjects demonstrate decreased allergen-induced T-cell proliferation and lower allergen-specific IgG antibody responses in comparison with patients with allergy.11Gurka G Ohman Jr, J Rosenwasser LJ. Allergen-specific human T cell clones: derivation, specificity, and activation requirements.J Allergy Clin Immunol. 1989; 83: 945-954Abstract Full Text PDF PubMed Scopus (16) Google Scholar One influence contributing to immune nonresponsiveness is diminished accessory cell function. In contrast to the asthmatic lung, the resident antigen-presenting cell population of the healthy lung is unable to present allergen to T helper lymphocytes and cannot stimulate cellular activation and proliferation.12Spiteri MA Knight RA Jeremy JY et al.Alveolar macrophage-induced suppression of peripheral blood mononuclear cell responsiveness is reversed by in vitro allergen exposure in bronchial asthma.Eur Respir J. 1994; 7: 1431-1438Crossref PubMed Scopus (41) Google Scholar The cytokine milieu of the nonasthmatic respiratory tract may also help mitigate proinflammatory responses. The normal respiratory tract is characterized by elevated concentrations of IL-10,13Borish L Aarons A Rumbyrt J Cvietusa P Negri J Wenzel S. Interleukin-10 regulation in normal subjects and patients with asthma.J Allergy Clin Immunol. 1996; 97: 1288-1296Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar which may be derived from airway macrophages and respiratory epithelial cells.14Bonfield TL Konstan MW Burfeind P Panuska JR Hilliard JB Berger M Normal bronchial epithelial cells constitutively produce the anti-inflammatory cytokine interleukin-10, which is downregulated in cystic fibrosis.Am J Respir Cell Mol Biol. 1995; 13: 257-261Crossref PubMed Scopus (325) Google Scholar This antiinflammatory cytokine contributes to the downregulation of accessory cells and inhibits cytokine release.15Ding L, Linsley PS, Huang L-Y, Germain RN, Shevach EM. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol 151:1224-34.Google Scholar In the gastrointestinal tract the normal nonresponsive state is maintained by a different antiinflammatory cytokine, transforming growth factor-β, which may similarly prevent inflammation in the respiratory tract.16McCartney-Francis NL Wahl S Transforming growth factor beta: a matter of life and death.J Leukoc Biol. 1995; 55: 401-409Google Scholar In this issue of the Journal of Allergy and Clinical Immunology, Hamid et al.17Hamid QA Schotman E Jacobson MR Walker SM Durham SR. Increases in (IL-12) messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy.J Allergy Clin Immunol. 1997; 99: 254-260Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar report on the presence and modulation of IL-12 in the immune response to allergens and modulation of IL-12 with immunotherapy. IL-12 is the cytokine primarily responsible for the differentiation of naive undifferentiated lymphocytes into Th 1-like cells.18Manetti R Parronchi P Giudizi MG Piccini M-P Maggi E Trinchieri G et al.Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells.J Exp Med. 1993; 177: 1199-1204Crossref PubMed Scopus (1632) Google Scholar, 19Hsieh C-S Macatonia SE Tripp CS O'Garra A Murphy KM Development of Th1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages.Science. 1993; 260: 547-549Crossref PubMed Scopus (2856) Google Scholar, 20Seder RA Gazzinelli R Sher A Paul WE. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming.Proc Natl Acad Sci USA. 1993; 90: 10188-10192Crossref PubMed Scopus (950) Google Scholar, 21McKnight AJ Zimmer GJ Fogelman I Wolf SF Abbas AK Effects of IL-12 on helper T cell-dependent immune responses in vivo.J Immunol. 1994; 152: 2172-2179PubMed Google Scholar IL-12 also augments release of Th 1 cytokines22Chan SJ Perussia B Gupta JW Kobayashi M Pospisil M Young HA et al.Induction of interferon-γ production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers.J Exp Med. 1991; 173: 869-879Crossref PubMed Scopus (953) Google Scholar, 23Kubin M Kamoun M Trinchieri G. Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells.J Exp Med. 1994; 180: 211-222Crossref PubMed Scopus (345) Google Scholar and inhibits IL-4 synthesis by Th 2 T cells.24DeKruyff RH Fang Y Wolf SF Umetsu DT IL-12 inhibits IL-4 synthesis in keyhole limpet hemocyanin-primed CD4+ T cells through an effect on antigen-presenting cells.J Immunol. 1995; 154: 2578-2587PubMed Google Scholar, 25Marshall JD Secrist H DeKruyff RH Wolf SF Umetsu DT IL-12 inhibits the production of IL-4 and IL-10 in allergen-specific human CD4+ T lymphocytes.J Immunol. 1995; 155: 111-117PubMed Google Scholar Although IFN-γ is required as a secondary signal to induce the Th 1 phenotype, induction of IL-12 early in the immune response is the primary signal for Th 1 induction. One can imagine an increasingly complex picture in which the immune response to allergens in nonallergic subjects is characterized by a state of immune nonresponsiveness but also by the presence of IL-12–mediated induction of Th 1-like responses. Additional factors may include transforming growth factor-β and IL-10, which prevent the development of cellular inflammation. It is conceivable that a low-grade Th 1 response to allergens with IFN-γ secretion is needed to help control development of the Th 2 response. However, additional triggers that enhance IL-12 production will drive the immune response toward cellular inflammation such as that observed with Mycobacterium tuberculosis, sarcoidosis, and the interstitial lung diseases. In contrast, a milieu characterized by the presence of IL-4 and other factors directs immune responses into Th 2-driven allergic disorders. How then does immunotherapy fit into the delicate balance between tolerance and Th 1 or Th 2 response? Immunotherapy reduces IL-4 production through the induction of tolerance by Th 2 lymphocytes. Published data establish the ability of high-dose immunogenic peptides to render their specific T helper lymphocytes nonresponsive.26Trentham DE Dynesius-Trentham RA Orav EJ Combitchi D Lorenzo C Sewell KL et al.Effects of oral administration of type II collagen on rheumatoid arthritis.Science. 1993; 261: 1727-1729Crossref PubMed Scopus (578) Google Scholar, 27Weiner HL Mackin GA Matsui M Orav EJ Khoury SJ Dawson DM et al.Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis.Science. 1993; 259: 1321-1323Crossref PubMed Scopus (540) Google Scholar, 28Kang S-M Beverly B Tran A-C Brorson K Schwartz RH Lenardo MJ. Transactivation by AP-1 is a molecular target of T cell clonal anergy.Science. 1992; 257: 1134-1138Crossref PubMed Scopus (306) Google Scholar These studies have been extended to allergen immunotherapy, which has been shown to make allergen-specific T cells unresponsive with decreased proliferation and IL-4 production after exposure to allergen.29Higgins JA Lamb JR Marsh SGE Tonks S Hayball JD Rosen-Bronson S et al.Peptide-induced nonresponsiveness of HLA-DP restricted human T cells reactive with Dermatophagoides spp. (house dust mite).J Allergy Clin Immunol. 1992; 90: 749-756Abstract Full Text PDF PubMed Scopus (78) Google Scholar, 30Secrist H Chelen CJ Wen Y Marshall JD Umetsu DT. Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals.J Exp Med. 1993; 178: 2123-2130Crossref PubMed Scopus (551) Google Scholar, 31O'Hehir RE Lamb JR Induction of specific clonal anergy in human T lymphocytes by Staphylococcus aureus enterotoxins.Proc Natl Acad Sci USA. 1990; 87: 8884-8888Crossref PubMed Scopus (133) Google Scholar, 32Briner TJ Kuo M-C Keating KM Rogers BL Greenstein JL. Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen.Proc Natl Acad Sci USA. 1993; 90: 7608-7612Crossref PubMed Scopus (275) Google Scholar, 33McHugh SM Deighton J Stewart AG Lachmann PJ Ewan PW. Bee venom immunotherapy induces a shift in cytokine responses from a TH-2 to a TH-1 dominant pattern: comparison of rush and conventional immunotherapy.Clin Exp Allergy. 1995; 25: 828-838Crossref PubMed Scopus (182) Google Scholar The article by Hamid et al.17Hamid QA Schotman E Jacobson MR Walker SM Durham SR. Increases in (IL-12) messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy.J Allergy Clin Immunol. 1997; 99: 254-260Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar reports the enhanced production of IL-12 after 4 years of grass immunotherapy. Induction of IL-12 after a course of immunotherapy may have limited benefits through the capacity of IL-12 to decrease IL-4 production by Th 2 lymphocytes and to reduce Th 2 differentiation. The increased presence of IL-12 is consistent with published observations that Th 1-like cells are induced by immunotherapy.33McHugh SM Deighton J Stewart AG Lachmann PJ Ewan PW. Bee venom immunotherapy induces a shift in cytokine responses from a TH-2 to a TH-1 dominant pattern: comparison of rush and conventional immunotherapy.Clin Exp Allergy. 1995; 25: 828-838Crossref PubMed Scopus (182) Google Scholar, 34Varney VA Hamid QA Gaga M Ying S Jacobson M Frew AJ et al.Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses.J Clin Invest. 1993; 92: 644-651Crossref PubMed Scopus (470) Google Scholar, 35Jutel M Pichler WJ Skrbic D Urwyler A Dahinden C Muller UR Bee venom immunotherapy results in decrease of IL-4 and IL-5 increase of IFN-γ secretion in specific allergen-stimulated T cell cultures.J Immunol. 1995; 154: 4187-4194PubMed Google Scholar However, the belief that IL-12 and IFN-γ might be the basis for the beneficial effects of immunotherapy is tempered by three observations: (1) the asthmatic lung and allergic nose already contain IFN-γ, which clearly is not effectively lessening inflammation; (2) if it were useful for IFN-γ to be induced by immunotherapy, then therapeutic trials with IFN-γ would have shown clinical benefit, which they have not; and (3) IL-12 and IFN-γ do not behave like "magic bullets," which manage to inhibit IL-4 synthesis, IgE production, and Th 2 activity without simultaneously activating accessory cell function, inducing adhesion molecule expression, and stimulating neutrophils and eosinophils. Immunotherapy may therefore restore the state observed in nonallergic subjects with mixed populations of tolerized nonresponsive T helper lymphocytes and activated Th 1 lymphocytes. However, if true, this induction of IL-12/Th 1 responses—as opposed to the induction of tolerance—is not a desirable result and must be limited and controlled because excessive IL-12 production would be expected to induce cellular inflammation. It is therefore relevant that immunotherapy is also associated with upregulation of the antiinflammatory cytokines IL-10 and transforming growth factor-β.5Gaglani B Borish L Buchmeier A Keller L Nelson H. Local nasal immunotherapy (LNIT) with aqueous weed extract is an effective therapy for weed induced rhinitis.J Allergy Clin Immunol. 1996; 97 ([abstract]): 301Abstract Full Text PDF Google Scholar, 36Hawrylowicz CM Jarman ER Guida L O'Hehir RE Lamb JR T-cell receptor peptides that inhibit the T-cell response to allergen induce transforming growth factor-β 1 production.J Allergy Clin Immunol. 1996; 97: 707-709Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 37Chen Y Kuchroo VK Inobe J-i Hafler DA Weiner HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis.Science. 1994; 265: 1237-1240Crossref PubMed Scopus (1736) Google Scholar Overall, immunotherapy may promote immune tolerance by subtly regulating the cytokine milieu, rather than by redirecting inflammation from a Th 2 to a Th 1 pattern of response. The Th 1/Th 2 theory of tolerance in immunotherapy implies that there are two waves of infiltrating cells that respond to either the allergen or the immunotherapy (i.e., an initial infiltrate of Th 2 cells responding to the allergen and a subsequent wave of Th 1 cells migrating in to reverse the response in a secondary wave of treatment). The data for this do not exist in spite of in situ hybridization studies, such as that by Hamid et al.17Hamid QA Schotman E Jacobson MR Walker SM Durham SR. Increases in (IL-12) messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy.J Allergy Clin Immunol. 1997; 99: 254-260Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar What these findings seen on immunohistochemistry and in situ hybridization do suggest is a changing cytokine milieu that may permit outgrowth of a Th 1- or Th 2-like pattern of cells. Furthermore, it is entirely possible that cells other than T cells may be affected by or may contribute to this change in cytokine gene expression initiated by immunotherapy. Hence, tolerance may be generated in cells other than T cells, and the changed cytokine milieu may affect signaling and selection of cytokine gene usage in mast cells, basophils, or eosinophils as well. A final question to ask is whether IL-12 therapy itself should be recommended for patients with allergy. IL-12–mediated downregulation of Th 2 responses and the induction of Th 1-like cells may be beneficial. It is equally plausible, however, that this intensely proinflammatory cytokine may worsen the inflammation of the respiratory tract. By analogy, trials of IFN-γ in asthma proved to be disappointing, and IL-12 may only recapitulate these results. The more we learn about cytokines, the more complex their spectrum of action becomes. Each cytokine mediates a range of biologic activities, which may be either proinflammatory or antiinflammatory, depending on the concentration, responding cell type, and timing within the immune response. Attempts to reduce each cytokine to a limited function, such as has been attempted with the Th 1/Th 2 paradigm, do not reflect the pleiotropic nature of these proteins and although appealing in their simplicity, ignore the true complexities of immune regulation.
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