Multispecific responses by T cells expanded by endogenous self-peptide/MHC complexes.

Area of Science:

• Immunology
• T cell biology
• Self-antigen recognition

Background:

• Understanding the T cell response to self-peptides is crucial for distinguishing physiological from pathological immunity.
• The precise nature and breadth of T cell reactivity towards endogenous antigens remain incompletely understood.

Purpose of the Study:

• To directly investigate the human T cell response to endogenous self-peptides in healthy individuals.
• To characterize the antigen reactivity profile of T cells stimulated by self-antigens.

Main Methods:

• Healthy subjects' T cells were labeled with CFSE and stimulated with antigen-presenting cells carrying endogenous self-antigens.
• Proliferating (CFSE(low)) and non-proliferating (CFSE(high)) CD4+ T cell populations were single-cell sorted, cloned, and screened against self- and microbial antigens.
• TCRbeta chain sequencing was performed to confirm clonality.

Main Results:

• Approximately 0.04% of CD4+ T cells entered cell cycle upon stimulation with self-peptide/MHC complexes, dependent on CD28 costimulation.
• T cell clones derived from self-peptide stimulation (CFSE(low)) displayed significantly greater cross-reactivity to multiple antigens compared to other T cell populations.
• Sequencing confirmed that the self-peptide-reactive clones were indeed clonal.

Conclusions:

• T cell clones generated in response to endogenous self-peptides exhibit a high degree of multispecificity.
• This multispecificity may arise from the recognition of shared structural features within MHC molecules.