Could cross‐reactivity rescue Foxp3+ regulatory T cell precursors from thymic deletion?

Thymocytes that bind with high affinity to peptides displayed by MHC class II (pMHC‐II) are deleted while low‐affinity binders differentiate into naive CD4+ T cells. However, Foxp3+ regulatory T cells (Tregs) seem to defy this binary choice as their precursors require high‐affinity interaction with pMHC‐II for maturation in the thymus. Here, we rely on the antigen‐specific interpretive framework, SPIRAL (Specific ImmunoRegulatory Algorithm), to propose that Tregs escape thymic deletion by forming dyads with IL‐2‐producing T cells via antigen cross‐reactivity. This interpretation reconciles contradictions related to Treg ontogeny in the thymus and their role in modulating antigen‐specific immune responses.