CD8-positive, alpha-beta T cell lineage commitment

Definition

Target type: biologicalprocess

The process in which an immature T cell becomes committed to becoming a CD8-positive, alpha-beta T cell. [ISBN:0781735149]

CD8-positive, alpha-beta T cell lineage commitment is a complex and highly regulated process that begins in the bone marrow and continues in the thymus. It involves a series of steps that ultimately lead to the generation of mature CD8+ T cells capable of recognizing and eliminating virally infected cells and tumor cells. Here's a breakdown of the key steps:

**1. Commitment to the T Cell Lineage:**
* Hematopoietic stem cells (HSCs) in the bone marrow give rise to multipotent progenitors.
* These progenitors commit to the T cell lineage under the influence of specific cytokines like IL-7 and the transcription factor GATA3.

**2. Migration to the Thymus:**
* Committed T cell progenitors migrate from the bone marrow to the thymus, the primary organ of T cell development.

**3. Double-Negative (DN) Stage (CD4-CD8-)**
* In the thymus, T cell progenitors enter the DN stage, characterized by the absence of CD4 and CD8 co-receptors on their surface.
* This stage is further subdivided into four substages (DN1-DN4):
* DN1: Expression of CD44 and CD25
* DN2: Loss of CD44 but retains CD25
* DN3: Loss of CD25, initiates T cell receptor (TCR) beta chain rearrangement
* DN4: TCR beta chain rearrangement complete, expression of pre-TCR

**4. Pre-TCR Checkpoint:**
* During DN3 and DN4, TCR beta chain genes undergo VDJ recombination, generating a diverse repertoire of TCR beta chains.
* Successful rearrangement of the TCR beta chain results in the formation of a pre-TCR complex (consisting of TCR beta, pre-T alpha, CD3, and zeta chains).
* The pre-TCR complex signals to the cell, promoting proliferation and survival.
* Cells that fail to successfully rearrange the TCR beta chain undergo apoptosis.

**5. Double-Positive (DP) Stage (CD4+CD8+)**
* Cells that pass the pre-TCR checkpoint transition to the DP stage, expressing both CD4 and CD8 co-receptors.
* During the DP stage, TCR alpha chain gene rearrangement occurs.
* Successful rearrangement of the TCR alpha chain leads to the formation of a functional alpha-beta TCR complex on the cell surface.

**6. Positive Selection:**
* The DP stage is critical for positive selection.
* DP thymocytes encounter self-peptide-MHC complexes presented by thymic epithelial cells (TECs).
* Cells that successfully bind to self-MHC with moderate affinity receive survival signals and are allowed to progress further.
* Cells that fail to bind or bind too strongly undergo apoptosis.

**7. CD8 Lineage Commitment:**
* Cells that successfully pass positive selection enter a stage of lineage commitment, where they will become either CD4+ or CD8+ T cells.
* CD8 lineage commitment is influenced by the strength of TCR-MHC interaction and the presence of specific transcription factors.
* Thymocytes with TCRs that interact with MHC class I molecules are preferentially directed towards the CD8 lineage.

**8. Negative Selection:**
* After positive selection, CD8+ T cells undergo negative selection, where they are exposed to a wide variety of self-antigens.
* Cells that interact strongly with self-antigens undergo apoptosis, preventing the development of autoreactive T cells.

**9. Mature CD8+ T Cells:**
* T cells that successfully complete negative selection emerge from the thymus as mature, self-tolerant CD8+ T cells, capable of recognizing and eliminating virally infected cells and tumor cells.

**10. Peripheral T Cell Function:**
* Mature CD8+ T cells circulate in the blood and lymph, constantly surveying the body for signs of infection or malignancy.
* Upon encountering their cognate antigen presented by an MHC class I molecule on an infected or tumor cell, they activate, proliferate, and differentiate into cytotoxic T lymphocytes (CTLs).
* CTLs kill infected or tumor cells by releasing cytotoxic molecules like granzyme and perforin.

This intricate process ensures that the immune system generates a diverse repertoire of CD8+ T cells that are capable of recognizing and eliminating a wide range of pathogens and cancerous cells, while avoiding self-reactivity.'
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