What is the mechanism of T cell exhaustion, and which markers are commonly used to identify exhausted T cells?

• A. Chronic antigen exposure leads to reduced effector function; markers include PD-1, TIM-3, LAG-3.
• B. Acute antigen exposure leads to increased cytotoxicity; markers include CD28.
• C. Exhaustion results from apoptosis induced by B cell signals; markers include CD19.
• D. Exhaustion is caused by a lack of cytokines; markers include IL-2.

Answer: (A)

T cell exhaustion arises from ongoing antigen exposure, leading to a progressive loss of effector functions such as cytokine production and cytotoxicity while the cells acquire high levels of inhibitory receptors. This state is driven by persistent stimulation that reprograms signaling, transcriptional networks, and metabolism, locking T cells into a subdued but persistent form of dysfunction. Markers like PD-1 are hallmark indicators, and additional inhibitory receptors such as TIM-3 and LAG-3 are commonly upregulated on exhausted T cells, helping to identify them in contexts like chronic infections and tumors. The combination of reduced function and the expression of these inhibitory receptors is why this option best captures the mechanism and the typical markers used to identify exhausted T cells.

Choosing other descriptions would miss the core pattern: acute antigen exposure boosts activation and cytotoxicity (not exhaustion), CD28 is a costimulatory molecule associated with activation rather than exhaustion, CD19 is a B cell marker and not relevant to T cell exhaustion, and exhaustion isn’t simply due to a lack of cytokines like IL-2.