Antigen transfer in the thymus

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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. [1]

Contents

Thymus represents an origin of T cell development and its responsibility is to select functional but also safe T cells which will not attack self tissues. Self-harmful T cells, further referred to as autoreactive T cells, originate in the thymus because of the stochastic process called V(D)J recombination which conducts the generation of T cell receptors (TCRs) and enables their limitless variability. Two processes of central tolerance take place in thymic medulla, namely clonal deletion (recessive tolerance) and T Regulatory cells selection (dominant tolerance) which force autoreactive T cells to apoptosis or skew them into suppressor T regulatory cells (TRegs), respectively, in order to protect body against manifestations of autoimmunity.[ citation needed ]

These processes are mediated especially by unique subset of stromal cells called Medullary thymic epithelial cells (mTECs) via presentation of Tissue restricted antigens (TRAs) that represent self tissues from almost all parts of the body. [2]

mTECs

mTECs are not only capable to present TRAs as efficient APCs. They are also potent in production of these TRAs via unique process called promiscuous gene expression (PGE) [3] and might serve as their reservoir.

Drawbacks of antigen presentation

mTECs as APCs reveal some drawbacks on population level. Their numbers in thymic medulla reach only 100,000 per 2-week-old thymus. [4] Furthermore, average lifespan of mTECs does not exceed 2–3 days, [5] probably due to only known PGE activator Autoimmune regulator (Aire), [6] which requires for its proper function generation of DNA double strand breaks. [7] And last but not least, each TRA is expressed only by 1-3% of mTEC population. [8] These facts decrease the chance of efficient recessive or dominant tolerance.[ citation needed ]

Relevance of antigen transfer

Unidirectional spreading of mTEC-derived TRAs onto additional APCs via antigen transfer increases the probability of encounter between potential autoreactive T cell and its corresponding TRA and therefore enhances processes of central tolerance. Furthermore, antigen transfer enables TRA processing and presentation by different cellular microenvironments.

Despite relevance of antigen transfer, seminal study was published, showing mTECs to form fully established central tolerance without support of additional APCs. [9]

Antigen transfer enables indirect presentation of TRAs

First article which touches antigen transfer was published in 2004. Experiments from this study reveal that clonal deletion of autoreactive CD4+ T cells, apart from CD8+ T cells, requires indirect presentation of TRAs by bone marrow (BM) derived APCs. Direct presentation of TRAs by mTECs was shown to be insufficient in this case. [10] Requirement of indirect presentation of some mTEC-derived TRAs in the case of recessive tolerance was perceived also by additional studies which both firstly demonstrated antigen transfer as an instrument that enables this process. [11] [12] Need of TRA indirect presentation is probably closely related with above mentioned "processing of TRAs by different microenvironments".

N.B.: BM derived APCs don´t express TRAs, this process is uniquely dedicated to mTECs. Exception is represented by thymic B cells which were shown to express TRAs and Aire. [13] [14]

Thymic dendritic cells

Systemic ablation of dendritic cells (DCs) was shown to cause fatal manifestations of autoimmunity [15] which points to their importance in central tolerance. Indeed, as mTECs represent exclusive donors of TRAs, experiments with first antigen transfer mouse models discovered thymic dendritic cells (DCs) to be so far the only known TRAs acceptors involved in antigen transfer. [11] [12] Indispensability of DCs for the establishment of central tolerance was further verified by recent analysis, which revealed that DCs mediate both recessive and dominant tolerance, with preference for the latter, via presentation of more common TRAs. [16] [17]

Subsets

tDCs

The most efficient subset in TRA presentation and both modes of central tolerance was found to be CD8α+ thymic-derived DCs (tDCs). [16] This subset was also shown to express XCR1 and to be attracted by mTECs via XCL1 chemokine expression. [18] tDCs rise intrathymically and constitute approximately half of thymic DCs population. [19]

mDCs

Sirpα+ migratory DCs (mDCs) form second subset of thymic DCs. [20] They rise extrathymically, and were shown to present self antigens, especially blood-borne antigens, in the thymus, which they acquire in the periphery. [21] They were also shown to be more efficient in T regulatory cells selection than clonal deletion. [19]

pDCs

The last abundant subset of thymic DCs is represented by B220+ plasmacytoid DCs (pDCs) [20] which also rise extrathymically and transfer peripheral antigens from the periphery to the thymus to mediate selection processes. [22]

All these thymic DC subsets were shown to participate in antigen transfer. Nevertheless, only tDCs and mDCs were observed to utilize transferred TRAs for indirect presentation which led to the processes of central tolerance. [23]

Mechanism

The unambiguous mechanism of the antigen transfer is still unknown. However, there are three possible ways: I.acquisition of mTEC apoptotic bodies , which could possibly be related with low mTEC lifespan [5] II.acquisition of exosomes and III.acquisition via trogocytosis , how antigen transfer can be mediated. [11] [12] [23]

There is also an evidence, that antigen transfer and therefore indirect presentation by thymic DCs are regulated by PGE activator Aire. [24]

Related Research Articles

Dendritic cell Accessory cell of the mammalian immune system

Dendritic cells (DCs) are antigen-presenting cells of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems.

T cell White blood cells of the immune system

A T cell is a type of lymphocyte. T cells are one of the important 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.

Dr George Gordon MacPherson was Reader in Experimental Pathology, Turnbull Fellow, Tutor in Medicine, and Senior Tutor at Oriel College, Oxford. He held a Bachelor's degree (B.M.), Master's degree (M.A.) and a doctorate (D.Phil.). His research interests were in Cell Biology, Pathology, and Immunology. Medically qualified, he researched in the field of cellular immunology at the Sir William Dunn School of Pathology, University of Oxford.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

In the human immune system, central tolerance is the process of eliminating any developing T or B lymphocytes that are reactive to self. 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.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue 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.

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. Thymopoiesis describes the process which turns thymocytes into mature T cells according to either negative or positive selection. This selection process is vitally important in shaping the population of thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens but remain tolerant towards the body's own antigens. Positive selection selects cells which are able to bind MHC class I or II molecules with at least a weak affinity. This eliminates those T cells which would be non-functional due to an inability to bind MHC. Negative selection destroys thymocytes with a high affinity for self peptides or MHC. This eliminates cells which would direct immune responses towards self-proteins in the periphery. Negative selection is not 100% effective, and some autoreactive T cells escape and are released into the circulation. Additional mechanisms of peripheral tolerance exist to silence these cells, but if these fail, autoimmunity may arise.

Antigen presentation Vital immune process that is essential for T cell immune response triggering

Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, now bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation, where it can be recognized by a T-cell receptor. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

Autoimmune regulator Immune system protein

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids. AIRE is a transcription factor expressed in the medulla of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.

XCR1

The "C" sub-family of chemokine receptors contains only one member: XCR1, the receptor for XCL1 and XCL2.

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. 

CD83

CD83 is a human protein encoded by the CD83 gene.

Thymic stromal lymphopoietin

Thymic stromal lymphopoietin (TSLP) is a protein belonging to the cytokine family. It is known to play an important role in the maturation of T cell populations through activation of antigen-presenting cells.

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.

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.

Cortical thymic epithelial cells (cTECs) form unique parenchyma cell population of the thymus which critically contribute to the development of T cells.

Thymic epithelial cells (TECs) are specialized cells with high degree of anatomic, phenotypic and functional heterogeneity that are located in the outer layer (epithelium) of the thymic stroma. The thymus, as a primary lymphoid organ, mediates T cell development and maturation. The thymic microenvironment is established by TEC network filled with thymocytes in different developing stages. TECs and thymocytes are the most important components in the thymus, that are necessary for production of functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.

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.

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

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  22. ↑ Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A, Pachynski R, Nguyen L, Ghodsi A, Adler S, Butcher EC (March 2012). "Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance". Immunity. 36 (3): 438–50. doi:10.1016/j.immuni.2012.01.017. PMC   3315699 . PMID   22444632.
  23. 1 2 Kroger CJ, Spidale NA, Wang B, Tisch R (January 2017). "Thymic Dendritic Cell Subsets Display Distinct Efficiencies and Mechanisms of Intercellular MHC Transfer". Journal of Immunology. 198 (1): 249–256. doi:10.4049/jimmunol.1601516. PMC   5173434 . PMID   27895179.
  24. ↑ Hubert FX, Kinkel SA, Davey GM, Phipson B, Mueller SN, Liston A, Proietto AI, Cannon PZ, Forehan S, Smyth GK, Wu L, Goodnow CC, Carbone FR, Scott HS, Heath WR (September 2011). "Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance". Blood. 118 (9): 2462–72. doi: 10.1182/blood-2010-06-286393 . PMID   21505196.
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