Ontogeny

The process of development and maturation of the T Cells in mammals begins with the haematopoietic stem cells (HSC) in the fetal liver and later in the bone marrow where HSC differentiate into multipotent progenitors. A subset of multipotent progenitors initiates the transcription of recombination activating gene 1 and 2 (RAG 1 and RAG2) and become lymphoid-primed multipotent progenitors and then common lymphoid progenitors (CLP). Only a small subset of pluripotent cells migrates to the thymus and differentiates into early thymic progenitors (ETP). The thymus does not contain self-renewing progenitors; and therefore, long-term thymopoiesis depends on the recruitment of thymus-settling progenitors throughout the life of the individual (1). These progenitors must enter the thymus to become gradually reprogrammed into fully mature and functional T Cells. The T Cell’s distinct developmental steps, as illustrated in Figure 1, are coordinated with the migration of the developing thymocytes towards specific niches in the thymus that provide the necessary stage-specific factors that are needed for further differentiation.

The ETP are multipotent and can generate T Cells, B Cells, Natural killer cells (NK), myeloid cells, and dendritic cells (DC). ETP represent a small and heterogenous subset, have the ability to proliferate massively, and can be identified by the phenotype Linlow, CD25−, Kithigh as well as by their expression of Flt3, CD24, and CCR9 (1). These cells, which are attracted by the chemokines CCL19 and CCL21, enter the thymus via the corticomedullar junction. In the stroma of the thymus, the ETP encounter a large number of ligands for the Notch receptors as well as growth factors such as Kit-ligand and IL-7 which trigger and support the differentiation and proliferation of these cells in the initial stages of T Cell development (2). Moreover, the expression of Notch-1 receptors and their interaction with Delta-like ligands is essential for the differentiation of the T Cells in the thymus and for the inhibition of the non-T Cell lineage development (3).

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Within the thymic cortex, ETP differentiate into double negative (DN) cells that do not express either CD4 or CD8 (i.e., CD4− and CD8−). Some authors consider the ETP a DN1 cell that later differentiates into DN2 when it acquires the CD25+ and CD44+ receptors. At this stage of development, the cells lose the B potential and begin to express proteins that are critical for the subsequent T Cell receptor (TCR) gene rearrangement such as RAG1 and RAG2. They also begin to express proteins necessary for TCR assembly and signaling as CD3 chains, kinases, and phosphatases such as LCK, ZAP70, and LAT (4). DN3 cells can take two divergent routes of differentiation. A cell can either express the αβ chains of the TCR and follow the process of selection to generate CD4+ or CD8+ T Cells or express the γδ chains to generate a subpopulation of γδ lymphocytes with special functional characteristics (5,6) (Table 1).

The expression of the β chain of TCR, at the DN3 stage, cascades the simultaneous expression of the CD4 and CD8 molecules and thus, the cells convert into double positives (DP), which constitutes the largest population of cells in the thymus (4,7). At this stage of maturation, the DP cells enter a control point known as positive selection to select the cells with functional TCRs that bind to self-peptides with intermediate affinity and avidity. For this, the epithelial cells of the thymic cortex “put the DP cells to the test” by presenting their own peptides in the context of the class I (HLA-I) and class II (HLA-II) HLA molecules. Only a fraction (1%-5%) of the DP cells, that express a TCR with intermediate affinity for these Ags persists by survival signals. DP cells incapable of binding HLA-I or HLA-II undergo apoptosis. Positive selection allows the differentiation of the DP thymocytes towards a single positive (SP) population that is restricted to HLA (i.e., DP cells that recognize HLA-I differentiate into CD4−CD8+ and those that recognize HLA-II differentiate into CD4+CD8−) (8, 9). Subsequently, SP cells enter the medulla of the thymus where a second control point known as negative selection takes place. At the medulla, positively selected thymocytes are exposed to a diverse set of self-antigens presented by medullary thymic epithelial cells (mTEC) and DC. mTECs use a special epigenetic mechanism to give rise to what is often referred to as promiscuous gene expression which contributes to the low expression of many genes including tissue-restricted self-antigens. SP cells with a high affinity or avidity for binding self peptides presented on HLA-I or HLA-II are eliminated by apoptosis, thus assuring the destruction of potentially autoreactive cells (9). Cells that survive negative selection mature and become naïve T Cells given the fact that they have not been primed by Ag for which they express a specific TCR. Naïve T Cells leave the thymus and migrate continuously to the secondary lymphoid organs to be primed and differentiate into effector cells with specialized phenotypes.

Source: https://t-tees.com
Category: WHICH