Peripheral tolerance

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Peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery (after T and B cells egress from primary lymphoid organs). Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease.[1]

Mechanisms of peripheral tolerance include direct inactivation of effector T cells by either clonal deletion, conversion to regulatory T cells (Tregs) or induction of anergy.[2] Tregs, which are also generated during thymic T cell development, further suppress the effector functions of conventional lymphocytes in the periphery.[3] Dependence of a particular antigen on either central or peripheral tolerance is determined by its abundance in the organism.[4] B cell peripheral tolerance is much less studied and is largely mediated by B cell dependence on T cell help (see split tolerance below).

Ignorance[edit]

Antigens, which are present in generally low amount can be ignored by the immune system without any further mechanism, since T cells have to be activated, prior to their migration to non-lymphoid tissues.[4][5] Specialized mechanisms ensuring ignorance by immune system have developed in so called immunopriviliged organs.[2]

Immunopriviliged organs[edit]

Potentially self-reactive T-cells are not activated at immunoprivileged sites, where antigens are expressed in non-surveillanced areas. This can occur in the testes, for instance. Anatomical barriers can separate the lymphocytes from the antigen, an example is the central nervous system (the blood-brain-barrier). Naive T-cells are not present in high numbers in peripheral tissue, but stay mainly in the circulation and lymphoid tissue.

Some antigens are at too low a concentration to cause an immune response – a subthreshold stimulation will lead to apoptosis in a T cell.

These sites include the brain, the anterior chamber of the eye, the testes and the fetus. These areas are protected by several mechanisms: Fas-ligand expression binds Fas on lymphocytes inducing apoptosis, anti-inflammatory cytokines (including TGF-beta and interleukin 10) and blood-tissue-barrier with tight junctions between endothelial cells.

In the placenta indoleamine 2,3-dioxygenase (IDO) breaks down tryptophan, creating a "tryptophan desert" micro environment which inhibits lymphocyte proliferation.

Antigen-specific mechanisms[edit]

Although the majority of self-reactive T cell clones are deleted in the thymus by the mechanisms of central tolerance, low affinity self-reactive T cells continuously escape to the immune periphery.[4] Therefore, additional mechanisms exist to remove self-reactive T cells from the repertoire in the immune periphery.

Clonal deletion and Treg conversion[edit]

Dendritic cells (DCs) are a major cell population responsible for the initiation of adaptive immune response.[1] However, immature DCs are able to induce both CD4 and CD8 tolerance. These immature DCs acquire the antigen from the peipheral tissues (by endocytosis of apoptotic cells) and present it to the naive T cells in the secondary lymphoid organs. If the T cell recognizes the antigen, it is either deleted or converted to Treg.[6] Furthermore a BTLA+ DCs were identified as a specialized population of antigen presenting cells (APCs), responsible for Treg conversion.[7] Nonetheless, upon maturation (for example during the infection) DCs largely loose their tolerogenic capabilities.[6]

Aside from dendritic cells, aditional cell populations were identified, that are able to induce antigen-specific T cell tolerance. These are mainly the members of lymph node stromal cells (LNSCs). LNSCs are generally divided into several sub-populations based on the expression of gp38 (PDPN) and CD31 surface markers.[8] Among those, only fibroblastic reticular cells and lymph node stromal cells were shown to play a role in the peripheral tolerance. Both of those populations are able to induce CD8 T cell tolerance by presentation of the endogenous antigens on MHCI molecules [9][10] and even the CD4 T cell tolerance by the presentation of the peptide-MHCII complexes, which they acquired from the DCs.[11]

Suppression[edit]

Another mechanism which protects the body from autoimmune reactions is the suppression of self-reactive effector T cells by Tregs. Tregs can be generated either in the thymus during the negative selection or in the immune periphery by the mechanisms described above. Those generated in the thymus are called natural Tregs (nTergs) and the ones genereted in the periphery are called induced Tregs (iTregs). Regardless of their origin, once present Tregs use several different mechanisms to suppress autoimmune reactions. These include depletion of IL-2 from the environment and secretion of tolerogenic cytokines IL-10 and TGF-β.[3]

Induced anergy[edit]

T-cells can be made non-responsive to antigens presented if the T-cell engages an MHC molecule on an antigen presenting cell (signal 1) without engagement of costimulatory molecules (signal 2). Co-stimulatory molecules are upregulated by cytokines in the context of acute inflammation. Without pro-inflammatory cytokines, co-stimulatory molecules will not be expressed on the surface of the antigen presenting cell, and so anergy will result if there is an MHC-TCR interaction between the T cell and the APC.[2]

Split tolerance[edit]

Since many pathways of immunity are interdependent, they do not all need to be tolerised. For example, tolerised T cells will not activate autoreactive B cells. Without this help from CD4 T cells, the B cells will not be activated.[1]

References[edit]

  1. ^ a b c Janeway, Charles (2001-01-01). Immunobiology Five. Garland Pub. ISBN 9780815336426. 
  2. ^ a b c Mueller, Daniel L. "Mechanisms maintaining peripheral tolerance". Nature Immunology. 11 (1): 21–27. doi:10.1038/ni.1817. 
  3. ^ a b Cretney, Erika; Kallies, Axel; Nutt, Stephen L. "Differentiation and function of Foxp3+ effector regulatory T cells". Trends in Immunology. 34 (2): 74–80. doi:10.1016/j.it.2012.11.002. 
  4. ^ a b c Malhotra, Deepali; Linehan, Jonathan L; Dileepan, Thamotharampillai; Lee, You Jeong; Purtha, Whitney E; Lu, Jennifer V; Nelson, Ryan W; Fife, Brian T; Orr, Harry T; Anderson, Mark S; Hogquist, Kristin A; Jenkins, Marc K. "Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms, according to self-peptide expression patterns". Nature Immunology. 17 (2): 187–195. doi:10.1038/ni.3327. PMC 4718891Freely accessible. PMID 26726812. 
  5. ^ Masopust, David; Schenkel, Jason M. "The integration of T cell migration, differentiation and function". Nature Reviews Immunology. 13 (5): 309–320. doi:10.1038/nri3442. 
  6. ^ a b Steinman, Ralph M.; Hawiger, Daniel; Nussenzweig, Michel C. (2003-04-01). "Tolerogenic dendritic cells". Annual Review of Immunology. 21 (1): 685–711. doi:10.1146/annurev.immunol.21.120601.141040. ISSN 0732-0582. 
  7. ^ Jones, Andrew; Bourque, Jessica; Kuehm, Lindsey; Opejin, Adeleye; Teague, Ryan M.; Gross, Cindy; Hawiger, Daniel. "Immunomodulatory Functions of BTLA and HVEM Govern Induction of Extrathymic Regulatory T Cells and Tolerance by Dendritic Cells". Immunity. 45 (5): 1066–1077. doi:10.1016/j.immuni.2016.10.008. PMC 5112132Freely accessible. PMID 27793593. 
  8. ^ Koning, Jasper J.; Mebius, Reina E. "Interdependence of stromal and immune cells for lymph node function". Trends in Immunology. 33 (6): 264–270. doi:10.1016/j.it.2011.10.006. 
  9. ^ Fletcher, Anne L.; Lukacs-Kornek, Veronika; Reynoso, Erika D.; Pinner, Sophie E.; Bellemare-Pelletier, Angelique; Curry, Mark S.; Collier, Ai-Ris; Boyd, Richard L.; Turley, Shannon J. (2010-04-12). "Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions". Journal of Experimental Medicine. 207 (4): 689–697. doi:10.1084/jem.20092642. ISSN 0022-1007. PMC 2856033Freely accessible. PMID 20308362. 
  10. ^ Cohen, Jarish N.; Guidi, Cynthia J.; Tewalt, Eric F.; Qiao, Hui; Rouhani, Sherin J.; Ruddell, Alanna; Farr, Andrew G.; Tung, Kenneth S.; Engelhard, Victor H. (2010-04-12). "Lymph node–resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation". Journal of Experimental Medicine. 207 (4): 681–688. doi:10.1084/jem.20092465. ISSN 0022-1007. PMC 2856027Freely accessible. PMID 20308365. 
  11. ^ Dubrot, Juan; Duraes, Fernanda V.; Potin, Lambert; Capotosti, Francesca; Brighouse, Dale; Suter, Tobias; LeibundGut-Landmann, Salomé; Garbi, Natalio; Reith, Walter (2014-06-02). "Lymph node stromal cells acquire peptide–MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance". Journal of Experimental Medicine. 211 (6): 1153–1166. doi:10.1084/jem.20132000. ISSN 0022-1007. PMC 4042642Freely accessible. PMID 24842370.