The plasticity and dynamism in the immune responses to both self and environmental stimulation promote the maintenance and adaptation of a system that tends to harmoniously survive and evolve. Fluctuating antigenic forces coexist within the immune system and oscillate between order and chaos to the equilibrium. Thus, when mounting a response to internal or environmental antigens, the main host responses can be divided into two immunological categories. The first, a well-adapted mechanism of complex multi-cellular organisms classically known as tolerance, promotes persistent immunological responses. In the second, opposite way, the modulation of inflammatory immune responses occurs, which we call “intolerance”. Tolerance and intolerance can be mediated by humoral molecules, such as inflammatory compounds, complement, and antibodies, and by different cell types, such as sentinel cells, antigen-presenting cells, and cells that orchestrate the immune response. Tolerogenesis is important in vertebrates because it predisposes species to adapt to self and environmental negative-selective forces. This process depends, in large part, on antigenic co-stimulation (AgCS), which operates as a multi-integrated network formed by all immune and non-immune cells of the body that establishes tolerant immunoregulatory interactions from cells to cells and from cells to the environment. Antigenic distribution, quantity, nature, route of administration, and antigenic convergence on co-stimulatory pathways, and concurrent infections, and the presence of microorganisms (commensals and pathogens) in more than one site are important factors for activating AgCS. To conclude, the AgCS route is a natural immune response generated by heterogeneous APC profile with centralized regulation that promote the counterbalance between intolerant e tolerant status, which can have several applications in the medical and biological fields.
References
[1]
Mrass, P. and Weninger, W. (2006) Immune Cell Migration as a Means to Control Immune Privilege: Lessons from the CNS and Tumors. Immunological Reviews, 213, 195-212. https://doi.org/10.1111/j.1600-065X.2006.00433.x
[2]
Pfefferle, P.I. and Renz, H. (2014) Microbial Exposure and Onset of Allergic Diseases-Potential Prevention Strategies? Allergology International, 63, 3-10.
https://doi.org/10.2332/allergolint.13-RAI-0671
[3]
Singer, J.R. and Weaver, C.T. (2015.) Daughter’s Tolerance of Mom Matters in Mate Choice. Cell, 162, 467-469. https://doi.org/10.1016/j.cell.2015.07.030
[4]
Schjenken, J.E., Zhang, B., Chan, H.Y., Sharkey, D.J., Fullston, T. and Robertson, S.A. (2016) miRNA Regulation of Immune Tolerance in Early Pregnancy. American Journal of Reproductive Immunology, 75, 272-280.
https://doi.org/10.1111/aji.12490
[5]
Barton, B.M., Xu, R., Wherry, E.J. and Porrett, P.M. (2017) Pregnancy Promotes Tolerance to Future Offspring by Programming Selective Dysfunction in Long-Lived Maternal T Cells. Journal of Leukocyte Biology, 101, 975-987.
https://doi.org/10.1189/jlb.1A0316-135R
[6]
Markham, K.B., Rossi, K.Q., Nagaraja, H.N. and O’Shaughnessy, R.W. (2015) Hemolytic Disease of the Fetus and Newborn Due to Multiple Maternal Antibodies. American Journal of Obstetrics and Gynecology, 213, 68.e1-5.
https://doi.org/10.1016/j.ajog.2015.01.049
[7]
Hendrickson, J.E. and Delaney, M. (2016.) Hemolytic Disease of the Fetus and Newborn: Modern Practice and Future Investigations. Transfusion Medicine Reviews, 30, 159-164. https://doi.org/10.1016/j.tmrv.2016.05.008
[8]
Perry, J.S.A. and Hsieh, C.S. (2016) Development of T-Cell Tolerance Utilizes both Cell-Autonomous and Cooperative Presentation of Self-Antigen. Immunological Reviews, 271, 141-155. https://doi.org/10.1111/imr.12403
[9]
Fujino, M. and Li, X.-K. (2013) Role of STAT3 in Regulatory T Lymphocyte Plasticity during Acute Graft-vs.-Host-Disease. JAK-STAT, 2, e24529.
[10]
Ivanova, E.A. and Orekhov, A.N. (2015) T Helper Lymphocyte Subsets and Plasticity in Autoimmunity and Cancer: An Overview. BioMed Research International, 2015, Article ID: 327470. https://doi.org/10.1155/2015/327470
[11]
Shen, W., Hixon, J.A., McLean, M.H., Li, W.Q. and Durum, S.K. (2016) IL-22-Expressing Murine Lymphocytes Display Plasticity and Pathogenicity in Reporter Mice. Frontiers in Immunology, 6, 662.
https://doi.org/10.3389/fimmu.2015.00662
[12]
Tom, M.R., Li, J., Ueno, A., Fort Gasia, M., Chan, R., Hung, D.Y., et al. (2016) Novel CD8+ T-Cell Subsets Demonstrating Plasticity in Patients with Inflammatory Bowel Disease. Inflammatory Bowel Diseases, 22, 1596-608.
https://doi.org/10.1097/MIB.0000000000000848
[13]
Korn, T. and Kallies, A. (2017) T Cell Responses in the Central Nervous System. Nature Reviews Immunology, 17, 179-194. https://doi.org/10.1038/nri.2016.144
[14]
Belkaid, Y., Piccirillo, C. and Mendez, S. (2002) CD4 1 CD25 1 Regulatory T Cells Control Leishmania Major Persistence and Immunity. Nature, 420, 633-637.
https://doi.org/10.1038/nature01152
[15]
Cobbold, S. and Waldmann, H. (1998) Infectious Tolerance. Current Opinion in Immunology, 10, 518-524. https://doi.org/10.1016/S0952-7915(98)80217-3
[16]
Machado, A.P., Silva, M.R.R. and Fischman, O. (2010) Prolonged Infection by Fonsecaea pedrosoi after Antigenic Co-Stimulation at Different Sites in Experimental Murine Chromoblastomycosis. Virulence, 1, 29-36.
https://doi.org/10.4161/viru.1.1.9920
[17]
Mendonça, V.R.R., Queiroz, A.T.L., Lopes, F.M., Andrade, B.B. and Barral-Netto, M. (2013) Networking the Host Immune Response in Plasmodium vivax Malaria. Malaria Journal, 12, 69. https://doi.org/10.1186/1475-2875-12-69
[18]
Nair, P., Amsen, D. and Blander, J.M. (2011.) Co-Ordination of Incoming and Outgoing Traffic in Antigen-Presenting Cells by Pattern Recognition Receptors and T Cells. Traffic, 12, 1669-1676. https://doi.org/10.1111/j.1600-0854.2011.01251.x
[19]
Leitner, J., Grabmeier-Pfistershammer, K. and Steinberger, P. (2010) Receptors and Ligands Implicated in Human T Cell Costimulatory Processes. Immunology Letters, 128, 89-97. https://doi.org/10.1016/j.imlet.2009.11.009
[20]
Benson, M.J., Pino-Lagos, K., Rosemblatt, M. and Noelle, R.J. (2007) All-Trans Retinoic Acid Mediates Enhanced T Reg Cell Growth, Differentiation, and Gut Homing in the Face of High Levels of Co-Stimulation. The Journal of Experimental Medicine, 204, 1765-1774. https://doi.org/10.1084/jem.20070719
[21]
Rachamim, N., Gan, J., Segall, H., Krauthgamer, R., Marcus, H., Berrebi, A., et al. (1998) Tolerance Induction by “Megadose” Hematopoietic Transplants: Donor-Type Human CD34 Stem Cells Induce Potent Specific Reduction of Host Anti-Donor Cytotoxic T Lymphocyte Precursors in Mixed Lymphocyte Culture. Transplantation, 65, 1386-1393. https://doi.org/10.1097/00007890-199805270-00017
[22]
Taylor, P., Noelle, R.J. and Blazar, B.R. (2001) CD4(+)CD25(+) Immune Regulatory Cells Are Required for Induction of Tolerance to Alloantigen via Costimulatory Blockade. The Journal of Experimental Medicine, 193, 1311-1318.
https://doi.org/10.1084/jem.193.11.1311
[23]
Shafiani, S., Tucker-Heard, G., Kariyone, A., Takatsu, K. and Urdahl, K.B. (2010) Pathogen-Specific Regulatory T Cells Delay the Arrival of Effector T Cells in the Lung during Early Tuberculosis. The Journal of Experimental Medicine, 207, 1409-1420. https://doi.org/10.1084/jem.20091885
[24]
Cardona-Castro, N. and Agudelo-Flórez, P. (1999) Development of a Chronic Chromoblastomycosis Model in Immunocompetent Mice. Medical Mycology, 37, 81-83. https://doi.org/10.1080/02681219980000131
[25]
Cardona-Castro, N., Agudelo-Flórez, P. and Restrepo-Molina, R. (1996) Chromoblastomycosis Murine Model and in Vitro Test to Evaluate the Sensitivity of Fonsecaea pedrosoi to Ketoconazole, Itraconazole and Saperconazole. Memorias Do Instituto Oswaldo Cruz, 91, 779-784.
https://doi.org/10.1590/S0074-02761996000600026
[26]
Doetze, A., Satoguina, J., Burchard, G., Rau, T., Loliger, C., Fleischer, B., et al. (2000) Antigen-Specific Cellular Hyporesponsiveness in a Chronic Human Helminth Infection Is Mediated by Th3/Tr1-Type Cytokines IL-10 and Transforming Growth Factor-Beta But Not by a Th1 to Th2 Shift. International Immunology, 12, 623-630. https://doi.org/10.1093/intimm/12.5.623
[27]
Maizels, R.M., Sartono, E., Kurniawan, A., Partono, F., Selkirk, M.E. and Yazdanbakhsh, M. (1995) T-Cell Activation and the Balance of Antibody Isotypes in Human Lymphatic Filariasis. Parasitology Today, 11, 50-56.
https://doi.org/10.1016/0169-4758(95)80116-2
[28]
Pennycook, A., Openshaw, P. and Hussell, T. (2000) Partners in Crime: Co-Infections in the Developing World. Clinical and Experimental Immunology, 122, 296-299. https://doi.org/10.1046/j.1365-2249.2000.01407.x
[29]
Toes, R.E., Offringa, R., Blom, R.J., Melief, C.J. and Kast, W.M. (1996) Peptide Vaccination Can Lead to Enhanced Tumor Growth through Specific T-Cell Tolerance Induction. Proceedings of the National Academy of Sciences of the United States of America, 93, 7855-7860. https://doi.org/10.1073/pnas.93.15.7855
[30]
Burt, R.K., Slavin, S., Burns, W.H. and Marmont, A.M. (2002) Induction of Tolerance in Autoimmune Diseases by Hematopoietic Stem Cell Transplantation: Getting Closer to a Cure? Blood, 99, 768-784. https://doi.org/10.1182/blood.V99.3.768
[31]
Eberl, G. (2016) Immunity by Equilibrium. Nature Reviews Immunology, 16, 524-532. https://doi.org/10.1038/nri.2016.75
[32]
Ludvigsson, J. (2009) Adequate Doses of Autoantigen Administered using the Appropriate Route May Create Tolerance and Stop Autoimmunity. Diabetologia, 52, 175-176. https://doi.org/10.1007/s00125-008-1211-9
[33]
Zhang, N., Schröppel, B., Lal, G., Jakubzick, C., Mao, X., Chen, D., et al. (2009) Regulatory T Cells Sequentially Migrate from Inflamed Tissues to Draining Lymph Nodes to Suppress the Alloimmune Response. Immunity, 30, 458-469.
https://doi.org/10.1016/j.immuni.2008.12.022
[34]
Cong, Y., Feng, T., Fujihashi, K., Schoeb, T.R. and Elson, C.O. (2009) A Dominant, Coordinated T Regulatory Cell-IgA Response to the Intestinal Microbiota. Proceedings of the National Academy of Sciences, 106, 19256-19261.
https://doi.org/10.1073/pnas.0812681106
[35]
Akadegawa, K., Ishikawa, S., Sato, T., Suzuki, J., Yurino, H., Kitabatake, M., et al. (2005) Breakdown of Mucosal Immunity in the Gut and Resultant Systemic Sensitization by Oral Antigens in a Murine Model for Systemic Lupus Erythematosus. Journal of Immunology, 174, 5499-5506.
https://doi.org/10.4049/jimmunol.174.9.5499
[36]
Hart, A.L., Stagg, A.J., Frame, M., Graffner, H., Glise, H., Falk, P., et al. (2002) The Role of the Gut Flora in Health and Disease, and Its Modification as Therapy. Alimentary Pharmacology & Therapeutics, 16, 1383-1393.
https://doi.org/10.1046/j.1365-2036.2002.01310.x
[37]
Pennisi, E. (2009) Gut Reactions. Science, 324, 1136-1137.
https://doi.org/10.1046/j.1365-2036.2002.01310.x
[38]
Pennisi, E. (2011) Microbiology. Girth and the Gut (Bacteria). Science, 332, 32-33.
https://doi.org/10.1126/science.332.6025.32
[39]
Couzin-Frankel, J. (2010) Inflammation Bares a Dark Side. Science, 330, 1621.
https://doi.org/10.1126/science.330.6011.1621
[40]
Rosa, D.D., Dias, M.M.S., Grzeskowiak, L.M., Reis, S.A., Conceição, L.L. and Peluzio, M.C.G. (2017) Milk Kefir: Nutritional, Microbiological and Health Benefits. Nutrition Research Reviews, 30, 82-96. https://doi.org/10.1017/S0954422416000275
[41]
Graham, A.L., Hayward, A.D., Watt, K.A., Pilkington, J.G., Pemberton, J.M. and Nussey, D.H. (2010) Fitness Correlates of Heritable Variation in Antibody Responsiveness in a Wild Mammal. Science, 330, 662-665.
https://doi.org/10.1126/science.1194878
[42]
Kim, H.-J., Verbinnen, B., Tang, X., Lu, L. and Cantor, H. (2010) Inhibition of Follicular T-Helper Cells by CD8+ Regulatory T Cells Is Essential for Self Tolerance. Nature, 467, 328-332. https://doi.org/10.1038/nature09370
[43]
Kishi, Y. and Tsubata, T. (2009) Apoptosis of Marginal Zone B-Cells in Unimmunized Mice. Journal of Medical and Dental Sciences, 56, 49-54.
[44]
Katsura, Y., Kawaguchi, S. and Muramatsu, S. (1972) Difference in the Target Cells for Tolerance Induction in Relation to the Dose of Tolerogen. Immunology, 23, 537-544.
[45]
Zinkernagel, R.M. (2004) On Immunity against Infections and Vaccines: Credo 2004. Scandinavian Journal of Immunology, 60, 9-13.
https://doi.org/10.1111/j.0300-9475.2004.01460.x
[46]
Morecki, S., Leshem, B., Eid, A. and Slavin, S. (1987) Alloantigen Persistence in Induction and Maintenance of Transplantation Tolerance. The Journal of Experimental Medicine, 165, 1468-1480. https://doi.org/10.1084/jem.165.6.1468
[47]
Th. den Boer, A., Diehl, L., van Mierlo, G.J.D., van der Voort, E.I.H., Fransen, M.F., Krimpenfort, P., et al. (2001) Longevity of Antigen Presentation and Activation Status of APC Are Decisive Factors in the Balance between CTL Immunity versus Tolerance. The Journal of Immunology, 167, 2522-2528.
https://doi.org/10.4049/jimmunol.167.5.2522
[48]
Redmond, W.L., Marincek, B.C. and Sherman, L.A. (2005) Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance in Vivo. Journal of Immunology, 174, 2046-2053. https://doi.org/10.4049/jimmunol.174.4.2046
[49]
Machado, A.P., Regis Silva, M.R. and Fischman, O. (2011) Local Phagocytic Responses after Murine Infection with Different Forms of Fonsecaea pedrosoi and Sclerotic Bodies Originating from an Inoculum of Conidiogenous Cells. Mycoses, 54, 202-211. https://doi.org/10.1111/j.1439-0507.2009.01792.x
[50]
Brattig, N.W., Lepping, B., Timmann, C., Büttner, D.W., Marfo, Y., Hamelmann, C., et al. (2002) Onchocerca volvulus-Exposed Persons Fail to Produce Interferon-Gamma in Response to O. volvulus Antigen But Mount Proliferative Responses with Interleukin-5 and IL-13 Production That Decrease with Increasing Microfilarial Density. The Journal of Infectious Diseases, 185, 1148-1154.
https://doi.org/10.1086/339820
[51]
Sousa, M.G.T., Azevedo, C. d. M.P. e S., Nascimento, R.C., Ghosn, E.E.B., Santiago, K.L., Noal, V., et al. (2008) Fonsecaea pedrosoi Infection Induces Differential Modulation of Costimulatory Molecules and Cytokines in Monocytes from Patients with Severe and Mild Forms of Chromoblastomycosis. Journal of Leukocyte Biology, 84, 864-870. https://doi.org/10.1189/jlb.0308211
[52]
Duong, B.H., Tian, H., Ota, T., Completo, G., Han, S., Vela, J.L., et al. (2010) Decoration of T-Independent Antigen with Ligands for CD22 and Siglec-G Can Suppress Immunity and Induce B Cell Tolerance in Vivo. The Journal of Experimental Medicine, 207, 173-187. https://doi.org/10.1084/jem.20091873
[53]
Watanabe, R., Ishiura, N., Nakashima, H., Kuwano, Y., Okochi, H., Tamaki, K., et al. (2010) Regulatory B Cells (B10 Cells) Have a Suppressive Role in Murine Lupus: CD19 and B10 Cell Deficiency Exacerbates Systemic Autoimmunity. The Journal of Immunology, 184, 4801-4809. https://doi.org/10.4049/jimmunol.0902385
[54]
Yanaba, K., Bouaziz, J.-D., Matsushita, T., Tsubata, T. and Tedder, T.F. (2009) The Development and Function of Regulatory B Cells Expressing IL-10 (B10 Cells) Requires Antigen Receptor Diversity and TLR Signals. Journal of Immunology, 182, 7459-7472. https://doi.org/10.4049/jimmunol.0900270
[55]
Sato, K., Yoo, Y.C., Matsuzawa, K., Watanabe, R., Saiki, I., Tomo-Oka, S., et al. (1996) Tolerance to the Anti-Metastatic Effect of Lipopolysaccharide against Liver Metastasis in Mice. International Journal of Cancer, 66, 98-103.
https://doi.org/10.1002/(SICI)1097-0215(19960328)66:1<98::AID-IJC17>3.0.CO;2-7
[56]
Menges, M., Rössner, S., Voigtländer, C., Schindler, H., Kukutsch, N.A., Bogdan, C., et al. (2002) Repetitive Injections of Dendritic Cells Matured with Tumor Necrosis Factor Alpha Induce Antigen-Specific Protection of Mice from Autoimmunity. The Journal of Experimental Medicine, 195, 15-21.
https://doi.org/10.1084/jem.20011341
[57]
Voigtländer, C., Rössner, S., Cierpka, E., Theiner, G., Wiethe, C., Menges, M., et al. (2006) Dendritic Cells Matured with TNF Can Be Further Activated in Vitro and after Subcutaneous Injection in Vivo Which Converts Their Tolerogenicity into Immunogenicity. Journal of Immunotherapy, 29, 407-415.
https://doi.org/10.1097/01.cji.0000210081.60178.b4
[58]
Sammons, M.L., Stephen, E.L., Levy, H.B., Baron, S. and Hilmas, D.E. (1977) Interferon Induction in Cynomolgus and Rhesus Monkey after Repeated Doses of a Modified Polyriboinosinic-Polyribocytidylic Acid Complex. Antimicrobial Agents and Chemotherapy, 11, 80-83. https://doi.org/10.1128/AAC.11.1.80
[59]
Sundstrom, J.B. and Cherniak, R. (1992) The Glucuronoxylomannan of Cryptococcus Neoformans Serotype A Is a Type 2 T-Cell-Independent Antigen. Infection and Immunity, 60, 4080-4087.
[60]
Campbell, J.D., Buckland, K.F., McMillan, S.J., Kearley, J., Oldfield, W.L.G., Stern, L.J., et al. (2009) Peptide Immunotherapy in Allergic Asthma Generates IL-10-Dependent Immunological Tolerance Associated with Linked Epitope Suppression. The Journal of Experimental Medicine, 206, 1535-1547.
https://doi.org/10.1084/jem.20082901
[61]
Talmadge, J.E., Herberman, R.B., Chirigos, M.A., Maluish, A.E., Schneider, M.A., Adams, J.S., et al. (1985) Hyporesponsiveness to Augmentation of Murine Natural Killer Cell Activity in Different Anatomical Compartments by Multiple Injections of Various Immunomodulators Including Recombinant Interferons and Interleukin 2. Journal of Immunology, 135, 2483-2491.
[62]
Dai, Y.D., Carayanniotis, G. and Sercarz, E. (2005) Antigen Processing by Autoreactive B Cells Promotes Determinant Spreading. Cellular & Molecular Immunology, 2, 169-175.
[63]
Sundstedt, A., Dohlsten, M., Hedlund, G., Hoiden, I., Bjorklund, M. and Kalland, T. (1994) Superantigens anergize Cytokine Production But Not Cytotoxicity in Vivo. Immunology, 82, 117-125.
[64]
Belfrage, H., Dohlsten, M., Hedlund, G. and Kalland, T. (1995) Enhanced and Prolonged Efficacy of Superantigen-Induced Cytotoxic T Lymphocyte Activity by Interleukin-2 in Vivo. Cancer Immunology Immunotherapy, 41, 87-94.
https://doi.org/10.1007/BF01527404
[65]
Hedlund, G., Dohlsten, M., Petersson, C. and Kalland, T. (1993) Superantigen-Based Tumor Therapy: In Vivo Activation of Cytotoxic T Cells. Cancer Immunology, Immunotherapy, 36, 89-93. https://doi.org/10.1007/BF01754407
[66]
Belfrage, H., Dohlsten, M., Hedlund, G. and Kalland, T. (1997) Prevention of Superantigen-Induced Down-Regulation of T-Cell Mediated Cytotoxic Activity by IL-2 in Vivo. Immunology, 90, 183-188.
https://doi.org/10.1046/j.1365-2567.1997.00030.x
[67]
Ghoreschi, K., Laurence, A., Yang, X.P., Tato, C.M., McGeachy, M.J., Konkel, J.E., et al. (2010) Generation of Pathogenic T(H)17 Cells in the Absence of TGF-Beta Signalling. Nature, 467, 967-971. https://doi.org/10.1038/nature09447
[68]
Maizels, R.M. and Yazdanbakhsh, M. (2003) Immune Regulation by Helminth Parasites: Cellular and Molecular Mechanisms. Nature Reviews Immunology, 3, 733-744. https://doi.org/10.1038/nri1183
[69]
Smits, H.H. and Yazdanbakhsh, M. (2007) Chronic Helminth Infections Modulate Allergen-Specific Immune Responses: Protection against Development of Allergic Disorders? Annals of Medicine, 39, 428-439.
https://doi.org/10.1080/07853890701436765
[70]
Figueiredo, C.A., Barreto, M.L., Rodrigues, L.C., Cooper, P.J., Silva, N.B., Amorim, L.D., et al. (2010) Chronic Intestinal Helminth Infections Are Associated with Immune Hyporesponsiveness and Induction of a Regulatory Network. Infection and Immunity, 78, 3160-3167. https://doi.org/10.1128/IAI.01228-09
[71]
Miller, C.M.D., Smith, N.C., Ikin, R.J., Boulter, N.R., Dalton, J.P. and Donnelly, S. (2009) Immunological Interactions between 2 Common Pathogens, Th1-Inducing Protozoan Toxoplasma gondii and the Th2-Inducing Helminth Fasciola Hepatica. PLoS ONE, 4, e5692. https://doi.org/10.1371/journal.pone.0005692
[72]
Burt, R.K., Abinun, M., Farge-Bancel, D., Fassas, A., Hiepe, F., Havrdova, E., Ikehara, S., Loh, Y., Marmont du Haut Champ, A., Voltarelli, J.C. and Snowden, J. (2010) Risks of Immune System Treatments. Science, 328, 825-826.
https://doi.org/10.1126/science.328.5980.825-e
[73]
Raghuvanshi, S., Sharma, P., Singh, S., Van Kaer, L. and Das, G. (2010) Mycobacterium Tuberculosis Evades Host Immunity by Recruiting Mesenchymal Stem Cells. Proceedings of the National Academy of Sciences, 107, 21653-21658.
https://doi.org/10.1073/pnas.1007967107
