Mixed Messages from Signal 2: Activating and Suppressive Costimulatory Molecules

Costimulatory signals play a crucial role in determining whether a CD4+ T cell will be activated or suppressed upon interaction with antigen-presenting cells (APCs). The balance between activating and inhibitory signals is essential for regulating immune responses and maintaining immune homeostasis. Several key ligand-receptor pairs are involved in these processes:

Activating Costimulatory Molecules:

1. CD28:B7-1 (CD80) and B7-2 (CD86): CD28 on T cells interacts with B7-1 and B7-2 molecules on APCs. This interaction provides a potent costimulatory signal necessary for T cell activation, proliferation, and cytokine production.
2. CD40:CD40L (CD154): CD40 on APCs engages with CD40 ligand (CD40L or CD154) on activated T cells. This interaction is crucial for the induction of effective immune responses, including B cell activation, class-switching, and memory formation.

Suppressive Costimulatory Molecules:

1. CTLA-4:B7-1 (CD80) and B7-2 (CD86): Cytotoxic T-lymphocyte antigen 4 (CTLA-4) competes with CD28 for binding to B7 molecules on APCs but delivers inhibitory signals to T cells upon engagement. CTLA-4 binding leads to suppression of T cell activation, proliferation, and cytokine production, thereby dampening immune responses.
2. PD-1:PD-L1 (B7-H1) and PD-L2 (B7-DC): Programmed death 1 (PD-1) expressed on T cells interacts with its ligands PD-L1 and PD-L2, which are expressed on APCs and other immune cells. PD-1 engagement delivers inhibitory signals to T cells, leading to T cell exhaustion, anergy, or apoptosis, thereby suppressing immune responses.

The factors controlling whether costimulatory molecules will exert activating or suppressive effects depend on various factors, including:

• Expression Levels: The balance between activating and inhibitory receptors on T cells and APCs, as well as the expression levels of their ligands, can determine the outcome of T cell activation. High levels of activating costimulatory molecules relative to inhibitory molecules may favor T cell activation, whereas the reverse may lead to T cell suppression.
• Microenvironmental Factors: The local cytokine milieu and other environmental cues at the site of T cell activation influence the expression and function of costimulatory molecules. Inflammatory cytokines may upregulate activating costimulatory molecules or induce the expression of suppressive molecules, thereby modulating T cell responses accordingly.
• Regulatory Mechanisms: Intracellular signaling pathways downstream of costimulatory receptors play critical roles in determining T cell fate. Positive signaling pathways, such as those involving PI3K/Akt and NF-κB, promote T cell activation, whereas negative regulatory pathways, such as those involving phosphatases and inhibitory receptors, counteract T cell activation and promote tolerance.

Overall, the balance between activating and inhibitory signals mediated by costimulatory molecules is finely regulated to ensure appropriate immune responses while preventing immune hyperactivity and autoimmunity.

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Source: ChatGPT response prompted and edited by Joel Graff.

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