CD28 costimulation regulates genome-wide effects on alternative splicing

Area of Science:

• Immunology
• Molecular Biology
• Gene Regulation

Background:

• CD28 is a key costimulatory receptor for naive T cell activation.
• TCR stimulation alone alters gene expression, but CD28's impact on transcription is limited.
• Alternative splicing generates proteomic diversity and tissue-specific gene regulation.

Purpose of the Study:

• To investigate the role of CD28 costimulation in alternative splicing during naive T cell activation.
• To compare the effects of CD28 on alternative splicing versus gene transcription.
• To elucidate the mechanism by which CD28 influences alternative splicing.

Main Methods:

• Analysis of gene expression and alternative splicing in T cells stimulated with TCR alone versus TCR plus CD28.
• Identification of over-represented biological processes in alternatively spliced genes.
• Assessment of hnRNPLL dependency and expression levels in response to CD28 signaling.

Main Results:

• CD28 costimulation induces substantial changes in alternative splicing, exceeding its transcriptional effects.
• Distinct biological processes are regulated by CD28-modulated alternative splicing compared to transcriptional changes.
• Genes regulated by hnRNPLL were enriched in TCR plus CD28 stimulated T cells.
• hnRNPLL expression is dependent on CD28 signaling.

Conclusions:

• CD28 costimulation primarily impacts T cell activation through extensive modulation of alternative splicing.
• Alternative splicing regulated by CD28 and hnRNPLL provides a novel mechanism for controlling T cell responses.
• This highlights a previously underappreciated role for CD28 in regulating alternative splicing during T cell activation.