Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression

Area of Science:

• Immunology
• Cancer Biology
• Cellular Immunology

Background:

• Stem-like T cells are vital for effective anti-cancer immunotherapy due to their proliferative and differentiation capabilities.
• Identifying these stem-like T cells and understanding their development is crucial for advancing cancer treatment.

Purpose of the Study:

• To identify key regulators of stem-like T cell populations.
• To understand the role of these regulators in T cell responses during chronic infection and cancer.
• To explore the therapeutic potential of targeting these stem-like T cells.

Main Methods:

• Investigated the role of the transcriptional regulator inhibitor of DNA binding 3 (ID3) in T cell populations during acute and chronic infections.
• Analyzed the generation of precursors of exhausted T (Tpex) cells.
• Examined the impact of ID3 expression and loss on CD8 T cell immunity and tumor control.
• Assessed the role of interleukin-1 (IL-1) family members (IL-36β, IL-18) in promoting ID3+ T cell generation.

Main Results:

• ID3 identifies stem-like T cells adapted to generate Tpex cells during acute infection.
• ID3 expression is essential for Tpex cells to sustain T cell responses in chronic infection and cancer.
• Loss of ID3 impairs the maintenance of CD8 T cell immunity.
• IL-36β and IL-18 promote the generation of ID3+ T cells, leading to enhanced tumor control.

Conclusions:

• ID3 is a critical regulator of stem-like T cells in both acute and chronic infections.
• ID3 is specifically required for sustaining T cell responses against chronic stimulation, such as in cancer.
• Targeting ID3+ T cells represents a promising strategy for improving anti-cancer immunotherapy.