“Old friends” induced local bystander regulation in the gut is difficult to reconcile with suppression of responses to airway allergens or autoimmune antigens present in distant body tissues. Microbial invasion will lead to local inflammatory stress and Tregs may become induced specific for microbial antigens and for heat shock proteins expressed under influence of cellular stress. While microbe-specific Tregs will produce local bystander suppression in the vicinity of the invasive organisms, HSP specific Treg will be able to find targets for suppression wherever inflammatory stress occurs in the body. Herewith, with HSP as a molecular basis of the hygiene hypothesis, infection-induced HSP upregulation may correlate inversely with immune inflammatory disorders.