Alternative splicing of apoptosis genes promotes human T cell survival

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Alternative splicing generates diverse mRNA and protein isoforms from most human genes.
• While T cell activation alters splicing, the functional consequences and regulatory mechanisms remain unclear.
• The role of CD28 costimulation in modulating T cell activation-induced alternative splicing is not well understood.

Purpose of the Study:

• To investigate the impact of CD28 costimulation on T cell receptor (TCR)-induced alternative splicing.
• To determine how CD28-modulated splicing events influence T cell function, particularly apoptosis resistance.
• To identify signaling pathways involved in CD28-enhanced alternative splicing.

Main Methods:

• T cell activation with and without CD28 costimulation.
• Analysis of alternative splicing events using CRISPR-edited cells and antisense oligonucleotides.
• Assessment of apoptosis resistance and cell viability.
• Investigation of the JNK signaling pathway.

Main Results:

• CD28 costimulation enhances TCR-induced alternative splicing for a subset of genes (up to 20%).
• CD28-enhanced splicing of caspase-9, Bax, and Bim isoforms promotes resistance to apoptosis.
• Combined changes in these three genes confer additive cell viability benefits.
• The JNK signaling pathway is essential for these CD28-costimulated splicing events.

Conclusions:

• Alternative splicing is a critical mechanism by which CD28 costimulation promotes activated T cell viability.
• CD28 signaling, in conjunction with TCR signaling, fine-tunes alternative splicing to enhance T cell survival.
• The JNK pathway integrates CD28 costimulation signals to regulate specific splicing events crucial for T cell function.