Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin

Area of Science:

• Immunology
• Cancer Biology
• Cellular Biology

Background:

• 4-1BB agonist antibody therapy is a promising cancer treatment.
• The precise mechanisms by which 4-1BB enhances anti-tumor immunity are not fully understood.
• A population of KLRG1(+) T cells is induced by 4-1BB agonist antibody treatment and infiltrates tumors.

Purpose of the Study:

• To investigate the origin and function of 4-1BB-induced KLRG1(+) T cells.
• To define the characteristics of this novel T cell phenotype.
• To explore the role of these T cells in both cancer and infectious immunity.

Main Methods:

• Flow cytometry and single-cell RNA sequencing to characterize T cell populations.
• In vivo studies using mouse models of melanoma and infectious diseases.
• Analysis of transcription factor expression (Eomesodermin) and cytokine production (IL-27, IL-15, IL-10).

Main Results:

• 4-1BB agonist antibody treatment induces a novel CD4(+) T cell phenotype with enhanced, multipotent cytotoxicity.
• This phenotype is driven by the transcription factor Eomesodermin, distinct from known T cell polarities.
• Formation requires 4-1BB signaling on T cells and antigen-presenting cells, leading to IL-27, IL-15, and IL-10 production.
• Similar T cell populations were identified in mice infected with intracellular pathogens, suggesting a role in infectious immunity.

Conclusions:

• 4-1BB activation generates a novel T cell subset with significant cytotoxic potential against tumors.
• This T cell phenotype is conserved in infectious immunity, highlighting its broad functional relevance.
• Understanding this novel T cell population clarifies 4-1BB's role in enhancing tumor cytotoxicity and balancing immunity and autoimmunity.