Dominant human CD8 T cell clonotypes persist simultaneously as memory and effector cells in memory phase.

Area of Science:

• Immunology
• T cell biology
• Adaptive immunity

Background:

• The adaptive immune system relies on memory T cells for robust secondary infection protection.
• Memory T cells are maintained long-term in a heterogeneous state after primary antigen encounter.

Purpose of the Study:

• To investigate the phenotypic heterogeneity and functional capacity of influenza-specific CD8 T cells in healthy humans.
• To determine if distinct memory and effector T cell populations coexist within the same antigen-specific repertoire.

Main Methods:

• Extensive phenotypic analysis of HLA-A*0201/influenza matrix protein(58-66)-specific CD8 T cells.
• Direct ex vivo assessment of target cell killing capacity.
• Sequencing of T cell receptor (TCR) alpha- and beta-chains.

Main Results:

• Up to 20% of influenza-specific CD8 T cells lacked IL-7 receptor CD127 and costimulatory molecule CD28, expressing effector molecules granzyme B and perforin.
• These CD28-negative cells demonstrated direct ex vivo antigen-specific cytotoxic activity.
• TCR sequencing revealed a limited repertoire dominated by few clonotypes per donor, with identical clonotypes found in both memory and effector T cell subsets.

Conclusions:

• Healthy humans harbor long-lived influenza-specific effector T cells alongside memory T cells.
• Identical T cell clonotypes can differentiate into both memory and effector lineages, supporting multipotent differentiation.
• Observed granzyme B expression suggests potential antigen-nonspecific bystander activation in influenza-specific CD8 T cells.