T cell receptor revision

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T-cell receptor revision (alternative term: antigen receptor editing) is a process in the peripheral immune system which is used by mature T cells to alter their original antigenic specificity based on rearranged T cell receptors (TCR). This process can lead either to continuous appearance of potentially self-reactive T cells in the body, not controlled by the central tolerance mechanism in the thymus [1] or better eliminate such self-reactive T cells [2] on the other hand and thus contributing to peripheral tolerance – the extent of each has not been completely understood yet. [3] [4] [5] This process occurs during follicular helper T cell formation in lymph node germinal centers. [6] [7]

Contents

T cell revision is achieved via reactivation of recombination enzymes RAG1 and/or RAG2 after T cell activation in the periphery and random recombination of their CDR sequences. Post-revision peripheral T cell repertoire is strengthening all essential features of self-tolerant and self-MHC-restricted T cell repertoire generated in the thymus while keeping all its hallmarks – reactivity towards foreign antigens and homeostatic proliferation in response to self-MHC, so-called tonic signaling. [5]

Background of T cell specificity regulation

The initial diversification processes (somatic V(D)J recombination or gene conversion and nucleotide addition) occur in the primary lymphoid organ (thymus) and lead to very high diversity (> 1014) of TCRs, which are able to recognize almost any antigenic structure/sequence. The paradigm of adaptive immunity is that a single T cell is educated only in thymus and at the exit from thymus it can express only a single TCR with unique and definitive antigen specificity which cannot be modified. It is not correct since dual receptor T cells do exist in the periphery and the single receptor T cells can modify its specificity or regain a second TCR there. [8] [9] [10] Those T cells recognizing self-structures (peptide/MHC complexes) are eliminated in the thymus immediately in a process of central tolerance, however it is not 100% effective again. As a result, there are many self-reactive T cells emigrating from thymus to the periphery and performing their effector functions there, including cytototoxic and helper activities, finally leading to autoimmunity. Peripheral tolerance is a mechanism controlling such autoreactive T cells in secondary lymphoid organs, blood circulation and all non-lymphoid tissues by different means. TCR revision process is generating much higher T cell plasticity in the development of the adaptive immune system than we have previously anticipated.

Evidence for TCR revision

Activation-dependent T cell revision process is part of peripheral tolerance mechanisms if the new TCR specificity loses its autoreactive specificity as described in mouse transgenic [11] and knock-in [12] [13] mouse models or in self-reactive conventional T cells in mouse [13] [14] or man. [15] Since this process is random, it might also lead to de novo appearance of autoreactive TCRs on initially non-self reactive T cells or even switch between T cell lineages such as T regulatory cells and Th17 cells [16] or gamma/delta and alpha/beta T cells. [17]

The current knowledge on antigen receptor editing both in T cells and B cells is far from complete, but it has an essential impact on the central dogma of immunology - the control of adaptive immune cells, their specificity and regulation.

Related Research Articles

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissues that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

Molecular mimicry is the theoretical possibility that sequence similarities between foreign and self-peptides are enough to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the prevalence of several peptide sequences which can be both foreign and self in nature, just a few crucial residues can activate a single antibody or TCR. This highlights the importance of structural homology in the theory of molecular mimicry. Upon activation, these "peptide mimic" specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity). Molecular mimicry is one of several ways in which autoimmunity can be evoked. A molecular mimicking event is more than an epiphenomenon despite its low probability, and these events have serious implications in the onset of many human autoimmune disorders.

A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

<span class="mw-page-title-main">CCL21</span> Mammalian protein found in Homo sapiens

Chemokine ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine, exodus-2, and secondary lymphoid-tissue chemokine (SLC). CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7. The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

In immunology, clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.

Thymic involution is the shrinking (involution) of the thymus with age, resulting in changes in the architecture of the thymus and a decrease in tissue mass. Thymus involution is one of the major characteristics of vertebrate immunology, and occurs in almost all vertebrates, from birds, teleosts, amphibians to reptiles, though the thymi of a few species of sharks are known not to involute. This process is genetically regulated, with the nucleic material responsible being an example of a conserved sequence — one maintained through natural selection since it arose in a common ancestor of all species now exhibiting it, via a phenomenon known to bioinformaticists as an orthologic sequence homology.

<span class="mw-page-title-main">Medullary thymic epithelial cells</span>

Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.

Antigen transfer in the thymus is the transmission of self-antigens between thymic antigen-presenting cells which contributes to the establishment of T cell central tolerance.

Promiscuous gene expression (PGE), formerly referred to as ectopic expression, is a process specific to the thymus that plays a pivotal role in the establishment of central tolerance. This phenomenon enables generation of self-antigens, so called tissue-restricted antigens (TRAs), which are in the body expressed only by one or few specific tissues. These antigens are represented for example by insulin from the pancreas or defensins from the gastrointestinal tract. Antigen-presenting cells (APCs) of the thymus, namely medullary thymic epithelial cells (mTECs), dendritic cells (DCs) and B cells are capable to present peptides derived from TRAs to developing T cells and hereby test, whether their T cell receptors (TCRs) engage self entities and therefore their occurrence in the body can potentially lead to the development of autoimmune disease. In that case, thymic APCs either induce apoptosis in these autoreactive T cells or they deviate them to become T regulatory cells, which suppress self-reactive T cells in the body that escaped negative selection in the thymus. Thus, PGE is crucial for tissues protection against autoimmunity.

Virtual memory T cells (TVM) are a subtype of T lymphocytes. These are cells that have a memory phenotype but have not been exposed to a foreign antigen. They are classified as memory cells but do not have an obvious memory function. They were first observed and described in 2009. The name comes from a computerized "virtual memory" that describes a working memory based on an alternative use of an existing space.

Cd1-restricted T cells are part of the unconventional T cell family, they are stimulated by exposure to CD1+ antigen presenting cells (APCs). Many CD1-restricted T cells are rapidly stimulated to carry out helper and effector functions upon interaction with CD1-expressing antigen-presenting cells. CD1-restricted T cells regulate host defence, antitumor immunity and the balance between tolerance and autoimmunity.

Thymus stromal cells are subsets of specialized cells located in different areas of the thymus. They include all non-T-lineage cells, such as thymic epithelial cells (TECs), endothelial cells, mesenchymal cells, dendritic cells, and B lymphocytes, and provide signals essential for thymocyte development and the homeostasis of the thymic stroma.

References

  1. ↑ Vaitaitis, Gisela M.; Poulin, Michelle; Sanderson, Richard J.; Haskins, Kathryn; Wagner, David H. (Apr 1, 2003). "Cutting edge: CD40-induced expression of recombination activating gene (RAG) 1 and RAG2: a mechanism for the generation of autoaggressive T cells in the periphery". Journal of Immunology. 170 (7): 3455–3459. doi: 10.4049/jimmunol.170.7.3455 . ISSN   0022-1767. PMID   12646605.
  2. ↑ Simmons, Kalynn B.; Wubeshet, Maramawit; Ames, Kristina T.; McMahan, Catherine J.; Hale, J. Scott; Fink, Pamela J. (2012). "Modulation of TCRβ surface expression during TCR revision". Cellular Immunology. 272 (2): 124–129. doi:10.1016/j.cellimm.2011.10.022. ISSN   1090-2163. PMC   3244515 . PMID   22138498.
  3. ↑ Mostoslavsky, Raul; Alt, Frederick W. (Jun 2004). "Receptor revision in T cells: an open question?". Trends in Immunology. 25 (6): 276–279. doi:10.1016/j.it.2004.04.001. ISSN   1471-4906. PMID   15145316.
  4. ↑ Wagner, David H. (Apr 2007). "Re-shaping the T cell repertoire: TCR editing and TCR revision for good and for bad". Clinical Immunology (Orlando, Fla.). 123 (1): 1–6. doi:10.1016/j.clim.2006.08.006. ISSN   1521-6616. PMID   16990051.
  5. 1 2 Hale, J. Scott; Fink, Pamela J. (Apr 2010). "T-cell receptor revision: friend or foe?". Immunology. 129 (4): 467–473. doi:10.1111/j.1365-2567.2010.03250.x. ISSN   1365-2567. PMC   2842493 . PMID   20201984.
  6. ↑ Cooper, Cristine J.; Turk, Gail L.; Sun, Mingyi; Farr, Andrew G.; Fink, Pamela J. (Dec 1, 2004). "Cutting edge: TCR revision occurs in germinal centers". Journal of Immunology. 173 (11): 6532–6536. doi: 10.4049/jimmunol.173.11.6532 . ISSN   0022-1767. PMID   15557142.
  7. ↑ Higdon, Lauren E.; Deets, Katherine A.; Friesen, Travis J.; Sze, Kai-Yin; Fink, Pamela J. (Apr 15, 2014). "Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions". Proceedings of the National Academy of Sciences of the United States of America. 111 (15): 5652–5657. Bibcode:2014PNAS..111.5652H. doi: 10.1073/pnas.1321803111 . ISSN   1091-6490. PMC   3992682 . PMID   24706795.
  8. ↑ He, Xin; Janeway, Charles A.; Levine, Matthew; Robinson, Eve; Preston-Hurlburt, Paula; Viret, Christophe; Bottomly, Kim (Feb 2002). "Dual receptor T cells extend the immune repertoire for foreign antigens". Nature Immunology. 3 (2): 127–134. doi:10.1038/ni751. ISSN   1529-2908. PMID   11812989. S2CID   23163549.
  9. ↑ Morris, Gerald P.; Allen, Paul M. (Jun 1, 2009). "Cutting edge: Highly alloreactive dual TCR T cells play a dominant role in graft-versus-host disease". Journal of Immunology. 182 (11): 6639–6643. doi:10.4049/jimmunol.0900638. ISSN   1550-6606. PMC   3196624 . PMID   19454656.
  10. ↑ Ni, Peggy P.; Solomon, Benjamin; Hsieh, Chyi-Song; Allen, Paul M.; Morris, Gerald P. (Aug 15, 2014). "The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires". Journal of Immunology. 193 (4): 1778–1786. doi:10.4049/jimmunol.1400532. ISSN   1550-6606. PMC   4119549 . PMID   25015825.
  11. ↑ McMahan, C. J.; Fink, P. J. (November 1998). "RAG reexpression and DNA recombination at T cell receptor loci in peripheral CD4+ T cells". Immunity. 9 (5): 637–647. doi: 10.1016/s1074-7613(00)80661-5 . ISSN   1074-7613. PMID   9846485.
  12. ↑ Huang, Ching-Yu; Golub, Rachel; Wu, Gillian E.; Kanagawa, Osami (Apr 1, 2002). "Superantigen-induced TCR alpha locus secondary rearrangement: role in tolerance induction". Journal of Immunology. 168 (7): 3259–3265. doi: 10.4049/jimmunol.168.7.3259 . ISSN   0022-1767. PMID   11907080.
  13. 1 2 Takase, Mitsuyo; Kanagawa, Edith M.; Kanagawa, Osami (Aug 15, 2007). "Age-dependent TCR revision mediated by interaction between alphabeta TCR and self-antigens". Journal of Immunology. 179 (4): 2163–2169. doi: 10.4049/jimmunol.179.4.2163 . ISSN   0022-1767. PMID   17675475.
  14. ↑ Bynoe, Margaret S.; Viret, Christophe; Flavell, Richard A.; Janeway, Charles A. (Feb 22, 2005). "T cells from epicutaneously immunized mice are prone to T cell receptor revision". Proceedings of the National Academy of Sciences of the United States of America. 102 (8): 2898–2903. Bibcode:2005PNAS..102.2898B. doi: 10.1073/pnas.0409880102 . ISSN   0027-8424. PMC   549496 . PMID   15708975.
  15. ↑ Lantelme, Erica; Orlando, Luca; Porcedda, Paola; Turinetto, Valentina; De Marchi, Mario; Amoroso, Antonio; Mantovani, Stefania; Giachino, Claudia (Jan 2008). "An in vitro model of T cell receptor revision in mature human CD8+ T cells". Molecular Immunology. 45 (2): 328–337. doi:10.1016/j.molimm.2007.06.153. ISSN   0161-5890. PMID   17659780.
  16. ↑ Zehn, Dietmar; Bevan, Michael J.; Fink, Pamela J. (Nov 1, 2007). "Cutting edge: TCR revision affects predominantly Foxp3 cells and skews them toward the Th17 lineage". Journal of Immunology. 179 (9): 5653–5657. doi:10.4049/jimmunol.179.9.5653. ISSN   0022-1767. PMC   2776039 . PMID   17947636.
  17. ↑ Ziegler, Hendrik; Welker, Christian; Sterk, Marco; Haarer, Jan; Rammensee, Hans-Georg; Handgretinger, Rupert; Schilbach, Karin (2014). "Human Peripheral CD4(+) Vδ1(+) γδT Cells Can Develop into αβT Cells". Frontiers in Immunology. 5: 645. doi: 10.3389/fimmu.2014.00645 . ISSN   1664-3224. PMC   4329445 . PMID   25709606.
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