CD8-positive, alpha-beta T cell differentiation

Definition

Target type: biologicalprocess

The process in which a relatively unspecialized T cell acquires specialized features of a mature CD8-positive, alpha-beta T cell. [ISBN:0781735149]

CD8-positive, alpha-beta T cell differentiation is a complex process that begins in the bone marrow and culminates in the development of mature, cytotoxic T lymphocytes (CTLs) capable of recognizing and eliminating virally infected or cancerous cells. This process involves several stages, each characterized by distinct molecular changes and interactions:

**1. Commitment to the T cell lineage:**
- Hematopoietic stem cells (HSCs) in the bone marrow undergo differentiation into multipotent progenitors (MPPs).
- MPPs commit to the lymphoid lineage, giving rise to common lymphoid progenitors (CLPs).
- CLPs express the transcription factor Notch1, which directs them toward the T cell lineage.

**2. Double-negative (DN) thymocyte development:**
- CLPs migrate to the thymus, where they become DN thymocytes.
- DN thymocytes are characterized by the absence of both CD4 and CD8 coreceptors.
- DN thymocytes progress through four distinct stages (DN1-DN4) defined by the expression of CD44 and CD25.
- **DN1 (CD44+CD25-)**: Initial commitment to the T cell lineage, marked by the expression of CD44, a marker for hematopoietic progenitors.
- **DN2 (CD44+CD25+)**: Proliferation and expression of CD25 (IL-2 receptor alpha chain), indicating responsiveness to IL-2 signaling.
- **DN3 (CD44-CD25+)**: Rearrangement of the TCRbeta locus, leading to the generation of a pre-TCR, which signals for proliferation and survival.
- **DN4 (CD44-CD25-)**: Expression of the pre-TCR and commitment to the CD8 lineage.

**3. Double-positive (DP) thymocyte development:**
- DN4 cells upregulate both CD4 and CD8 coreceptors, becoming DP thymocytes.
- DP thymocytes undergo TCRalpha chain rearrangement, resulting in the expression of a complete TCR complex.
- The TCR interacts with self-peptides presented by MHC molecules expressed on thymic stromal cells.
- This interaction triggers a process called positive selection, where thymocytes with TCRs that can bind weakly to self-MHC are allowed to survive.
- The strength of TCR-MHC interactions influences the fate of DP thymocytes.

**4. Single-positive (SP) thymocyte development:**
- DP thymocytes that pass positive selection undergo negative selection.
- **Negative selection** eliminates thymocytes with TCRs that bind strongly to self-MHC, preventing autoimmunity.
- The outcome of negative selection determines the final fate of the thymocyte:
- **CD8 lineage**: Thymocytes with TCRs that interact primarily with MHC class I are directed to the CD8 lineage, becoming CD8 SP thymocytes.
- **CD4 lineage**: Thymocytes with TCRs that interact primarily with MHC class II are directed to the CD4 lineage, becoming CD4 SP thymocytes.
- SP thymocytes undergo further differentiation, acquiring mature CTL characteristics.

**5. Mature CD8+ T cell differentiation:**
- Mature CD8+ T cells are capable of recognizing and eliminating virally infected or cancerous cells.
- They express a variety of effector molecules, including cytotoxic granules containing perforin and granzyme, which induce target cell apoptosis.
- Mature CD8+ T cells can also express cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and lymphotoxin-alpha (LT-α), which contribute to the elimination of infected or cancerous cells.
- Memory CD8+ T cells are generated during the immune response, providing long-term protection against previously encountered pathogens.

**Key transcription factors involved in CD8 T cell differentiation:**

- **Notch1**: Promotes T cell lineage commitment.
- **GATA-3**: Essential for CD4 lineage commitment.
- **Runx3**: Essential for CD8 lineage commitment.
- **Foxo1**: Regulates TCR signaling and promotes CD8 differentiation.
- **Tcf7**: Promotes the survival and differentiation of CD8+ T cells.
- **Bcl11b**: Suppresses CD4 lineage commitment and promotes CD8 lineage development.
- **ThPOK**: Promotes CD4 lineage commitment and suppresses CD8 lineage development.

**Summary:**

- The process of CD8-positive, alpha-beta T cell differentiation involves a series of developmental stages in the thymus, where thymocytes undergo TCR rearrangement, positive and negative selection, and ultimately differentiate into mature, cytotoxic T lymphocytes (CTLs).
- This differentiation process is driven by a complex interplay of signaling pathways, transcription factors, and cell-cell interactions, ensuring the generation of a diverse and functional T cell repertoire capable of effectively responding to a wide range of pathogens and tumor cells.'
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