Foxp3+ regulatory T cells (Tregs) control immune response to prevent immunopathology. However, unlike conventional T cells, it is hard to determine antigen-specificity of Foxp3+ Tregs in a random T cell pool. Tregs do not secrete anything unique and they do not even proliferate when exposed to antigens in vitro, two functional readouts that are still used as a gold standard for determining antigen-specificity of conventional T cells.
Hence, we have no clue as to antigen[epitope] specificity of vast majority of human Tregs. Specificity of T cells could be also determined by non-functional readout such as tetramer staining. This is what the authors in new PNAS paper have used to determine antigen-specificity of Tregs.
They found that adult human peripheral blood contains FOXP3+ T cells that stain with tetramers specific for self as well as nonself peptides (Flu, melanoma protein, HIV epitopes).
Interestingly, frequency of antigen[epitope]-specific FOXP3+ Tregs varied among donors, but they were, on average, equally distributed among self and nonself [epitope]-specific Tregs, except Flu HA epitope.
Finally, comparison of neonatal [cord blood] and adult blood revealed that actual number of [epitope]-specific Tregs / per ml of blood did not change much between newborn and adult indicating that most of Tregs tested in this study were generated already by the time of birth.
In summary, this study revealed that human peripheral blood contain Tregs specific for both self nonself antigens. Since tested donors were negative for some of the infection such as HSV, CMV or HIV, it begs the question what [cross-reactive?] antigens maintain CMV or HIV-specific Tregs in antigen-naive [antigen-unexposed] hosts?