The role of thymus in T cell repertoire generation and selection
Rewrite the provided post discussing on the role of thymus in T cell repertoire generation and selection.
The role of thymus in T cell repertoire generation and selection
The development of T cell happens in the thymus after hematopoietic progenitors developed in stem cells in bone marrow, it will emigrate to the thymus for maturation into naive T cells, where they form their specific markers such as TCR, CD3, CD4 or CD8. The majority of the cells that enter the thymus are unable to become a naive T cell will die by apoptosis. The thymus is an organ with two lopes formed of cortex and medulla. These thymic microenvironments will direct the T cell precursors differentiation and positive and negative selection to ensure the production of functional self-tolerant naïve T Cell. The activity of the thymus is mostly active during neonatal and pre-adolescent periods. However, it starts to decrease with ageing.
In the thymus cortex microenvironment, the hematopoietic progenitors are activated to T-cell antigen receptor (TCR) expressing CD4+ CD8+ called double-positive (DP) thymocytes. During early thymocytes development, the rearrangement of V(D)J TCRα and TCRβ genomic loci allow for diverse recognition specificities that contribute to the selection fate of these newly formed cortical DP thymocytes. The positive selection is a process where the TCRs that are expressed by DP thymocyte, shows a low-affinity interaction with self-peptide-associated major histocompatibility complex class I (MHC-I) or MHC class II (MHC-II) are protected from apoptosis by upregulating IL-7R and enhanced to differentiate to single-positive (SP) thymocyte expressing CD4+CD8– or CD4–CD8+.
These positively selected thymocytes will present chemokine receptor CCR7 on their surface and leave to the thymic medulla to their ligand which produced by a subpopulation called medullary thymic epithelial cells (mTECs). In the thymic medulla, variety of self-molecules such as tissue-specific self-proteins are produced by mTECs subpopulation along with dendritic cells (DCs). TCRs of the medulla thymocytes that strongly interact with the self- peptide-MHC complex will downregulate IL-7R and either become regularity T cell or sentenced to death by apoptosis. This process is called negative selection, where self-reactive thymocytes are deleted. Negative and positive selection processes are determined based on the TCR affinity with self-pMHC complex resulting in either death or survival. Moreover, TCR affinity act as a detrimental factor of the T cell lineage direction, for example, CD4+ helper cells or CD8+ killer T cells.
In the thymus cortex, cortical thymic epithelial cells (cTECs) present unique microenvironment that express MHC-I and MHC-II molecules for the formed T cells to go through positive selection by protein degradation machinery. In addition, it aids in the development of T-lymphoid cells into T-cell, such as providing T-lineage activators molecules. CD4+ T cells positive selection is promoted by MHC-II-associated self-peptides, which are formed by the proteolysis in the lumen of the endosomal-lysosomal system, which achieved by two abundant endosomal peptidases Cathepsin L and TSSP.
The regulation of MHC-II degradation and turnover controlled by March family E3 ubiquitin ligases. Stabilization of surface MHC-II in cTEC achieved by decreasing the March8-mediated MHC-II turnover, to maintain TCR continuous reaction which is essential for CD4+ positive selection. Another process that contributes to enhancing the receptors selection of CD4+ T cell is autophagy, promoting the synthesis of MHC-II-associated self-peptides by the degradation of cytoplasmic proteins. Positive selection of CD8+ promoted by MHC-I-associated self-peptides dependent on thymoproteasome. MHC-I-associated self-peptides are produced by the proteasome-degradation of cytoplasmic proteins. Thymoproteasome is expressed by cTECs, consist of the inclusion of β5t a catalytic subunit, in which thymoproteasome is a unique proteasome that is highly specific to the cTECs.
The medullary microenvironment will provide antigen-presenting cells such as mTECs and hematopoietic dendritic cells that interact with the thymocyte establishing self-tolerance in T- cells. The released mature naïve T-cells into the circulation are the cells that survived the medullary selection. Self-tolerance in T cell achieved by presenting self-antigen to newly formed T cells by promiscuous gene expression (pGE). The expression of pGE in mTECs is regulated by a nuclear protein Aire along with other partner proteins through inducing gene transcription by recruiting RNA polymerase II at silenced loci, developing promiscuousness in gene expression. In addition, the thymic medulla is filled with hematopoietic antigen- presenting cells (APCs) such as dendritic cells and B cells. These APCs also have the capacity to present self-antigen, to test whether the newly formed T cell TCRs would recognize the self- antigen. If this happens, APCs will promote apoptosis in these autoreactive T cells as a part of the negative selection or direct them to become T regulatory cells. The traffic in the medulla is regulated by many chemokines that are produced by mTECs and other cells. The positively selected thymocytes are maintained by CXCL12 and CCL25 that regulate the medulla migration. The release of naïve T cell into the circulation is maintained by S1P binding to sphingosine-1-phosphate receptor 1 (S1P1) which present on naïve T cells.
In conclusion, thymus microenvironments promote the production of self-protective T-cell by various types of machinery in cTECs by proteolysis and in mTECs by unique gene expression. Although This machinery differs in their processes, it will eventually lead to the formation of immunocompetent and self-tolerant naïve T cells.
