negative regulation of CD4-positive, alpha-beta T cell proliferation

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of CD4-positive, alpha-beta T cell proliferation. [GOC:obol]

Negative regulation of CD4-positive, alpha-beta T cell proliferation is a complex process that ensures proper immune homeostasis and prevents excessive T cell activation, which could lead to autoimmune diseases. This regulation involves a multifaceted network of signaling pathways, transcription factors, and inhibitory molecules, working in concert to fine-tune T cell responses.

Here's a detailed breakdown of the key mechanisms involved:

1. **Antigen Recognition and Initial Activation:**
- CD4-positive, alpha-beta T cells, also known as helper T cells, are crucial for orchestrating immune responses. They recognize antigens presented by antigen-presenting cells (APCs) through their T cell receptor (TCR).
- Upon antigen recognition, the TCR complex initiates a cascade of signaling events leading to T cell activation.

2. **Signaling Pathways:**
- **TCR signaling:** The TCR complex activates several downstream signaling pathways, including the PI3K/AKT, MAPK, and NF-κB pathways. These pathways control gene expression and cellular processes essential for T cell activation and proliferation.
- **Co-stimulatory signals:** In addition to TCR signaling, co-stimulatory molecules like CD28, ICOS, and OX40 play a crucial role in promoting T cell activation.

3. **Inhibitory Mechanisms:**
- **CTLA-4:** Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a crucial inhibitory receptor expressed on activated T cells. It competes with CD28 for binding to CD80/CD86 on APCs, effectively dampening TCR signaling and suppressing T cell activation.
- **PD-1:** Programmed cell death-1 (PD-1) is another inhibitory receptor upregulated on activated T cells. PD-1 interacts with its ligands, PD-L1 and PD-L2, expressed on various cells, including APCs, tumor cells, and even T cells themselves. PD-1 signaling inhibits T cell activation, proliferation, and cytokine production.
- **LAG-3:** Lymphocyte activation gene 3 (LAG-3) is another inhibitory receptor that binds to MHC class II molecules on APCs. LAG-3 engagement suppresses T cell activation and cytokine production, particularly in chronic infections and cancer.

4. **Transcriptional Regulation:**
- **Foxp3:** Forkhead box P3 (Foxp3) is a transcription factor that plays a central role in the development and function of regulatory T cells (Tregs). Tregs are specialized T cells that suppress the activity of other T cells, contributing to immune tolerance.
- **Transcriptional repression:** Several transcription factors, including Blimp-1, Egr2, and Maf, suppress the expression of genes involved in T cell activation and proliferation.

5. **Cytokine Modulation:**
- **IL-10:** Interleukin-10 (IL-10) is an immunosuppressive cytokine that inhibits T cell proliferation and promotes Treg development.
- **TGF-β:** Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine that can either promote or inhibit T cell proliferation depending on the context. It primarily acts as an inhibitory factor, suppressing T cell activation and promoting Treg differentiation.

6. **Apoptosis and Exhaustion:**
- **Apoptosis:** In the absence of appropriate signals or under conditions of sustained activation, T cells can undergo programmed cell death (apoptosis), eliminating potentially harmful cells.
- **T cell exhaustion:** Chronic antigen stimulation can lead to T cell exhaustion, a state characterized by reduced effector function and increased expression of inhibitory receptors like PD-1. Exhausted T cells contribute to immune evasion in chronic infections and cancer.

7. **Immune Homeostasis and Tolerance:**
- The complex interplay of these regulatory mechanisms ensures that immune responses are tightly controlled. By inhibiting excessive T cell activation and proliferation, negative regulation of CD4-positive, alpha-beta T cells is crucial for maintaining immune homeostasis and preventing autoimmune diseases.
- This regulation also contributes to immune tolerance, preventing the immune system from attacking self-tissues and maintaining a balance between immune responses and self-protection.

In summary, negative regulation of CD4-positive, alpha-beta T cell proliferation is a multi-layered process involving signaling pathways, inhibitory receptors, transcription factors, and cytokines. This intricate regulation ensures proper T cell activation, prevents autoimmune diseases, and contributes to immune homeostasis and tolerance.'
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Proteins (3)

Compounds (15)