TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2.

Area of Science:

• Immunology
• Cellular Biology
• Molecular Biology

Background:

• Naive CD4+ T lymphocytes differentiate into distinct T helper (Th) cell subsets upon encountering peptide:MHC class II (p:MHCII) complexes presented by dendritic cells (DCs).
• The affinity of the T-cell receptor (TCR) for p:MHCII is known to influence Th differentiation, but the underlying mechanisms remain incompletely understood.
• Interleukin-2 receptor (IL-2R) signaling is implicated in promoting Th1 and suppressing Tfh cell differentiation.

Purpose of the Study:

• To elucidate the mechanisms by which TCR affinity dictates Th cell differentiation outcomes.
• To investigate the role of IL-2R signaling and DC-T cell interactions in TCR affinity-driven Th cell fate decisions.
• To identify novel molecular regulators involved in TCR affinity-mediated Th cell differentiation.

Main Methods:

• Comparative analysis of mouse naive T cell differentiation biased by low-affinity versus high-affinity TCRs.
• Assessment of T cell interactions with distinct dendritic cell subsets (SIRPα+ and XCR1+) following bacterial infection.
• Quantitative analysis of IL-2R expression and gene expression profiling of novel differentiation regulators (Eef1e1, Gbp2) in T cells.

Main Results:

• Low-affinity TCRs preferentially induced T follicular helper (Tfh) cell differentiation, whereas high-affinity TCRs promoted Th1 or Th17 cell formation.
• No preferential interaction was observed between specific T cell affinities and IL-2-consuming (SIRPα+) or non-consuming (XCR1+) DCs.
• High-affinity T cells exhibited sustained IL-2R expression and upregulated expression of Eef1e1 and Gbp2 compared to low-affinity T cells.

Conclusions:

• TCR affinity influences Th cell differentiation not by dictating interactions with specific DC subsets, but through direct modulation of gene expression within naive T cells.
• Sustained IL-2R signaling and the expression of novel regulators like Eef1e1 and Gbp2 are key downstream events regulated by TCR affinity.
• These findings reveal a direct mechanism by which TCR affinity controls T cell fate decisions, impacting adaptive immune responses.