negative regulation of T cell proliferation

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the rate or extent of T cell proliferation. [GOC:jl]

Negative regulation of T cell proliferation is a complex process involving a variety of molecular mechanisms that suppress the growth and division of T lymphocytes. This process is essential for maintaining immune homeostasis and preventing excessive immune responses that can lead to autoimmune diseases. Here are some key mechanisms involved in negative regulation of T cell proliferation:

1. **Cytokine Signaling:**
* **Transforming growth factor-beta (TGF-β):** TGF-β is a potent immunosuppressive cytokine that inhibits T cell proliferation by inducing the expression of cell cycle inhibitors, such as p21 and p27. It also promotes the differentiation of T cells into regulatory T cells (Tregs), which actively suppress other T cells.
* **Interleukin-10 (IL-10):** IL-10 is another immunosuppressive cytokine that inhibits T cell proliferation by suppressing the production of pro-inflammatory cytokines like TNF-α and IFN-γ. It also promotes the differentiation of Tregs.
* **Interleukin-2 (IL-2):** Although IL-2 is generally known as a pro-proliferative cytokine for T cells, it can also have negative regulatory effects at high concentrations. High doses of IL-2 can induce the expression of the IL-2 receptor alpha chain (CD25), which leads to the activation of intracellular signaling pathways that inhibit T cell proliferation.

2. **Immune Checkpoint Molecules:**
* **CTLA-4:** CTLA-4 is a negative regulatory receptor expressed on activated T cells. It binds to the same ligands as CD28, a positive stimulatory receptor, but with a higher affinity. This competition for ligand binding blocks the activation signals needed for T cell proliferation.
* **PD-1:** PD-1 is another negative regulatory receptor expressed on activated T cells. It binds to the PD-L1 and PD-L2 ligands expressed on various cells, including tumor cells. Upon engagement, PD-1 inhibits T cell proliferation and cytokine production.

3. **Apoptosis:**
* **Fas/FasL:** Fas (CD95) is a death receptor expressed on T cells, and its ligand (FasL) is expressed on various cells, including activated T cells. When Fas binds to FasL, it triggers a cascade of intracellular signaling events leading to apoptosis, eliminating activated T cells.
* **TRAIL/TRAIL-R:** TRAIL (TNF-related apoptosis-inducing ligand) is a type II transmembrane protein that can induce apoptosis in cells expressing its receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5). These receptors are expressed on activated T cells and their engagement can lead to cell death.

4. **T Cell Exhaustion:**
* Chronic exposure to antigens, such as those found in tumors or chronic infections, can lead to T cell exhaustion. Exhausted T cells exhibit a decreased ability to proliferate and produce cytokines. This state is characterized by the upregulation of inhibitory receptors like PD-1 and CTLA-4, leading to impaired T cell function.

5. **Regulatory T Cells (Tregs):**
* Tregs are a specialized subset of T cells that suppress the activation and proliferation of other T cells. They express the transcription factor Foxp3 and produce immunosuppressive cytokines like IL-10 and TGF-β. Tregs play a crucial role in preventing autoimmunity and maintaining immune tolerance.

These mechanisms work together to ensure that T cell proliferation is tightly controlled, preventing excessive immune responses and maintaining immune homeostasis. Understanding the intricate interplay of these regulatory pathways is crucial for developing effective strategies to modulate T cell responses in various disease settings, including cancer immunotherapy and autoimmune diseases.'
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Proteins (13)

Compounds (194)