Redefining the Foreign Antigen and Self-Driven Memory CD4⁺ T-Cell Compartments via Transcriptomic, Phenotypic, and...

Area of Science:

• Immunology
• T cell biology
• Cellular immunology

Background:

• Conventional CD4+ T cells are divided into naive and memory compartments.
• Memory CD4+ T cells are thought to include foreign antigen-specific cells and antigen-independent memory-phenotype (MP) cells.
• Distinct markers for these subpopulations and heterogeneity within MP cells remain unclear.

Purpose of the Study:

• To identify phenotypic markers that distinguish foreign antigen-specific memory CD4+ T cells from MP CD4+ T cells.
• To investigate the heterogeneity of MP CD4+ T cells and define distinct subsets.
• To determine the functional relevance of identified MP CD4+ T cell subsets.

Main Methods:

• Combined single-cell RNA sequencing and flow cytometry.
• Phenotypic analysis of CD4+ T lymphocyte populations.
• Assessment of T cell subset responsiveness to cytokines and in vivo function.

Main Results:

• MP CD4+ T lymphocytes comprise four distinct subsets defined by CD127 and Sca1 expression (CD127hi Sca1lo, CD127hi Sca1hi, CD127lo Sca1hi, CD127lo Sca1lo), all expressing low Bcl2.
• Foreign antigen-specific memory cells are identified as CD127hi Sca1hi Bcl2hi.
• The CD127hi Sca1hi MP subset represents the most mature population, exhibits high responsiveness to Th1 cytokines, and can induce colitis.

Conclusions:

• MP CD4+ T lymphocytes are a unique, self-driven population distinct from foreign antigen-specific memory cells based on marker expression.
• MP CD4+ T cells consist of at least four distinct subsets.
• The mature CD127hi Sca1hi MP CD4+ T cell subset has functional relevance, including the potential to induce colitis.