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Naturally occurring CD4+CD25+ regulatory T cells (nTR) comprise a separate lineage of T cells that are essential for maintaining immunological tolerance to self. Here we demonstrate that the level of phosphorylation of the TCR ζ-chain is ∼1.5- to 4-fold higher in nTR as compared with CD4+CD25− T cells. The increased level of TCR ζ-chain phosphorylation is presumably secondary to their higher affinity for self, resulting in a stronger TCR signal as it was completely blocked by treatment with anti-MHC class II. The enhanced level of TCR ζ-chain phosphorylation was correlated with the capacity of nTR to develop non-specific suppressor effector function following culture with IL-2 or IL-4 in the absence of TCR stimulus. Thus, a sub-population of nTR is activated by recognition of self-peptide–MHC class II ligands in vivo, resulting in their capacity to be induced to mediate suppressor function in vitro in the absence of TCR stimulation. [ABSTRACT FROM AUTHOR]