Infectious tolerance

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Infectious tolerance is a term referring to a phenomenon where a tolerance-inducing state is transferred from one cell population to another. It can be induced in many ways; although it is often artificially induced, it is a natural in vivo process. [1] A number of research deal with the development of a strategy utilizing this phenomenon in transplantation immunology. The goal is to achieve long-term tolerance of the transplant through short-term therapy. [2]

Contents

History

The term "infectious tolerance" was originally used by Gershon and Kondo in 1970 [3] for suppression of naive lymphocyte populations by cells with regulatory function and for the ability to transfer a state of unresponsiveness from one animal to another. [4] Gershon and Kondo discovered that T cells can not only amplify but also diminish immune responses. [5] The T cell population causing this down-regulation was called suppressor T cells and was intensively studied for the following years (nowadays they are called regulatory T cells and are again a very attractive for research). [6] These and other research in the 1970s showed greater complexity of immune regulation, unfortunately these experiments were largely disregarded, as methodological difficulties prevented clear evidence. Later developed new tolerogenic strategies have provided strong evidence to re-evaluate the phenomenon of T cell mediated suppression, in particular the use of non-depleting anti-CD4 monoclonal antibodies, demonstrating that neither thymus nor clonal deletion is necessary to induce tolerance. [7] In 1989 was successfully induced classical transplantation tolerance to skin grafts in adult mice using antibodies blocking T cell coreceptors in CD4+ populations. [8] Later was shown that the effect of monoclonal antibodies is formation of regulatory T lymphocytes. [9] It has been shown that transfer of tolerance to other recipients can be made without further manipulation and that this tolerance transfer depends only on CD4+ T-lymphocytes. [10] Because second-generation tolerance arises in the absence of any monoclonal antibodies to CD4 or CD8, it probably represents a natural response of the immune system, which, once initiated, becomes self-sustaining. This ensures the long duration of once induced tolerance, for as long as the donor antigens are present. [11]

Mechanisms

Treg migrate to the grafted tissue. Activated Treg convert ATP released by inflamed tissues to adenosine via the ectoenzymes CD39 and CD73. Local adenosine could contribute to the initial "privileged" microenvironment. Treg also secrete TGF-b and IL-10 which inhibit the maturation and migration of dendritic cells (DC). These "decommissioned" DC can secrete catabolic enzymes for depletion of essential amino acids (EAA) and, therefore, induce apoptosis of effector T cells. Moreover, the "privileged" tissues could release pro-apoptotic galectin-9 which binds to TIM-3 expressed by effector T cells such as Th1 and Th17. This further amplifies the immunosuppressive microenvironment. Each of these components within the graft can further reinforce the local anti-inflammatory state such that any naive T cell, migrating into this area, will be converted to induced Treg (iTreg) through infectious tolerance. The iTreg then expand and further suppress immunity in the "privileged" microenvironment. Immunoregulation by regulatory T cells (Treg)..jpg
Treg migrate to the grafted tissue. Activated Treg convert ATP released by inflamed tissues to adenosine via the ectoenzymes CD39 and CD73. Local adenosine could contribute to the initial "privileged" microenvironment. Treg also secrete TGF-β and IL-10 which inhibit the maturation and migration of dendritic cells (DC). These "decommissioned" DC can secrete catabolic enzymes for depletion of essential amino acids (EAA) and, therefore, induce apoptosis of effector T cells. Moreover, the "privileged" tissues could release pro-apoptotic galectin-9 which binds to TIM-3 expressed by effector T cells such as Th1 and Th17. This further amplifies the immunosuppressive microenvironment. Each of these components within the graft can further reinforce the local anti-inflammatory state such that any naive T cell, migrating into this area, will be converted to induced Treg (iTreg) through infectious tolerance. The iTreg then expand and further suppress immunity in the "privileged" microenvironment.

During a tolerant state potential effector cells remain but are tightly regulated by induced antigen-specific CD4+ regulatory T cells (iTregs). Many subsets of iTregs play a part in this process, but CD4+CD25+FoxP3+ Tregs play a key role, because they have the ability to convert conventional T cells into iTregs directly by secretion of the suppressive cytokines TGF-β, IL-10 or IL-35, or indirectly via dendritic cells (DCs). [12] Production of IL-10 induces the formation of another population of regulatory T cells called Tr1. Tr1 cells are dependent on IL-10 and TGF-β as well as Tregs, but differ from them by lacking expression of Foxp3. [13] High IL-10 production is characteristic for Tr1 cells themselves and they also produce TGF-β. [14] In the presence of IL-10 can be also induced tolerogenic DCs from monocytes, whose production of IL-10 is also important for Tr1 formation. [15] These interactions lead to the production of enzymes such as IDO (indolamine 2,3-dioxygenase) that catabolize essential amino acids. This microenvironment with a lack of essential amino acids together with other signals results in mTOR (mammalian target of rapamycin) inhibition which, particularly in synergy with TGF-β, direct the induction of new FoxP3 (forkhead box protein 3) expressing Tregs. [16]

See also

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References

  1. ↑ Cobbold, S.; Waldmann, H. (October 1998). "Infectious tolerance". Current Opinion in Immunology. 10 (5): 518–524. doi:10.1016/S0952-7915(98)80217-3. ISSN   0952-7915. PMID   9794831.
  2. ↑ Kendal, Adrian R.; Waldmann, Herman (October 2010). "Infectious tolerance: therapeutic potential". Current Opinion in Immunology. 22 (5): 560–565. doi:10.1016/j.coi.2010.08.002. ISSN   1879-0372. PMID   20829013.
  3. ↑ Gershon, R. K.; Kondo, K. (December 1971). "Infectious immunological tolerance". Immunology. 21 (6): 903–914. ISSN   0019-2805. PMC   1408252 . PMID   4943147.
  4. ↑ Gershon, R. K. (1975). "A disquisition on suppressor T cells". Transplantation Reviews. 26: 170–185. doi:10.1111/j.1600-065x.1975.tb00179.x. ISSN   0082-5948. PMID   1101469. S2CID   39375586.
  5. ↑ Gershon, R. K.; Kondo, K. (May 1970). "Cell interactions in the induction of tolerance: the role of thymic lymphocytes". Immunology. 18 (5): 723–737. ISSN   0019-2805. PMC   1455602 . PMID   4911896.
  6. ↑ Sakaguchi, Shimon; Wing, Kajsa; Miyara, Makoto (November 2007). "Regulatory T cells - a brief history and perspective". European Journal of Immunology. 37 (Suppl 1): S116–123. doi: 10.1002/eji.200737593 . ISSN   0014-2980. PMID   17972355.
  7. ↑ Qin, S. X.; Wise, M.; Cobbold, S. P.; Leong, L.; Kong, Y. C.; Parnes, J. R.; Waldmann, H. (December 1990). "Induction of tolerance in peripheral T cells with monoclonal antibodies". European Journal of Immunology. 20 (12): 2737–2745. doi:10.1002/eji.1830201231. ISSN   0014-2980. PMID   1702726. S2CID   30354546.
  8. ↑ Qin, S. X.; Cobbold, S.; Benjamin, R.; Waldmann, H. (1989-03-01). "Induction of classical transplantation tolerance in the adult". The Journal of Experimental Medicine. 169 (3): 779–794. doi:10.1084/jem.169.3.779. ISSN   0022-1007. PMC   2189271 . PMID   2647894.
  9. ↑ Tilney, N. L.; Guttmann, R. D. (1997-10-15). "Effects of initial ischemia/reperfusion injury on the transplanted kidney". Transplantation. 64 (7): 945–947. doi: 10.1097/00007890-199710150-00001 . ISSN   0041-1337. PMID   9381538.
  10. ↑ Kahan, B. D. (December 1993). "Toward a rational design of clinical trials of immunosuppressive agents in transplantation". Immunological Reviews. 136: 29–49. doi:10.1111/j.1600-065X.1993.tb00653.x. ISSN   0105-2896. PMID   8132202. S2CID   45337367.
  11. ↑ Qin, S.; Cobbold, S. P.; Pope, H.; Elliott, J.; Kioussis, D.; Davies, J.; Waldmann, H. (1993-02-12). ""Infectious" transplantation tolerance". Science. 259 (5097): 974–977. Bibcode:1993Sci...259..974Q. doi:10.1126/science.8094901. ISSN   0036-8075. PMID   8094901. S2CID   40979501.
  12. ↑ Gravano, David M.; Vignali, Dario A.A. (June 2012). "The Battle Against Immunopathology: Infectious Tolerance Mediated by Regulatory T Cells". Cellular and Molecular Life Sciences. 69 (12): 1997–2008. doi:10.1007/s00018-011-0907-z. ISSN   1420-682X. PMC   3353028 . PMID   22205213.
  13. ↑ Roncarolo, Maria Grazia; Gregori, Silvia; Battaglia, Manuela; Bacchetta, Rosa; Fleischhauer, Katharina; Levings, Megan K. (August 2006). "Interleukin-10-secreting type 1 regulatory T cells in rodents and humans". Immunological Reviews. 212: 28–50. doi:10.1111/j.0105-2896.2006.00420.x. ISSN   0105-2896. PMID   16903904. S2CID   21297026.
  14. ↑ Mekala, Divya J.; Alli, Rajshekhar S.; Geiger, Terrence L. (2005-08-16). "IL-10-dependent infectious tolerance after the treatment of experimental allergic encephalomyelitis with redirected CD4+CD25+ T lymphocytes". Proceedings of the National Academy of Sciences of the United States of America. 102 (33): 11817–11822. Bibcode:2005PNAS..10211817M. doi: 10.1073/pnas.0505445102 . ISSN   0027-8424. PMC   1188008 . PMID   16087867.
  15. ↑ Gregori, Silvia; Tomasoni, Daniela; Pacciani, Valentina; Scirpoli, Miriam; Battaglia, Manuela; Magnani, Chiara Francesca; Hauben, Ehud; Roncarolo, Maria-Grazia (2010-08-12). "Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway". Blood. 116 (6): 935–944. doi: 10.1182/blood-2009-07-234872 . ISSN   1528-0020. PMID   20448110.
  16. ↑ Cobbold, Stephen P.; Adams, Elizabeth; Nolan, Kathleen F.; Regateiro, Frederico S.; Waldmann, Herman (July 2010). "Connecting the mechanisms of T-cell regulation: dendritic cells as the missing link". Immunological Reviews. 236: 203–218. doi:10.1111/j.1600-065X.2010.00913.x. ISSN   1600-065X. PMID   20636819. S2CID   42889594.
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