The immune system has evolved a variety of regulatory mechanisms to ensure the peripheral self-tolerance as wellas the optimal capacity to elicit effective anti-infection immunity.At present,there is no satisfactory conceptualframework to explain how the peripheral immunity is regulated at a biological system level,which enables theimmune system to perform its essential functions to mount effective immunity to virtually any foreign antigens butavoid harmful immune responses to self.In this regard,during the past few years,an“affinity/avidity model ofperipheral T cell regulation”has been proposed and tested,which opens up a new paradigm to understand how theperipheral immunity,to both self and foreign antigens,is regulated.The paradigm is based on the discovery of asubset CD8~+ T cells with TCRs which specifically recognize a unique set of self-peptides presented by the MHCclass Ib molecule Qa-1 differentially expressed on T cells as a function of the affinity/avidity of T cell activation.These Qa-1 restricted CD8~+ T cells represent an example of how the immune system utilizes a unified mechanismto regulate adaptive immunity to both self and foreign antigens.Thus,by selectively down-regulating T cells ofintermediate affinity/avidity,to any antigens,the immune system controls the adaptive immunity without thenecessity to distinguish self from non-self in the periphery at the level of T cell regulation.Cellular & MolecularImmunology.2005;2(3):161-167. The immune system has evolved a variety of regulatory mechanisms to ensure the peripheral self-tolerance as wellas the optimal capacity to elicit effective anti-infection immunity. At present, there is no satisfactory conceptual framework to explain how the peripheral immunity is regulated at a biological system level, which enables theimmune system to perform its essential functions to mount effective immunity to virtually any foreign antigens butavoid8 immune immune responses to self.In this regard, during the past few years, an “affinity / avidity model of peripheral T cell regulation” has been proposed and tested, which opens up a new paradigm to understand how theperipheral immunity, to both self and foreign antigens, is regulated.The paradigm based on the discovery of asubset CD8 ~ + T cells with TCRs which specifically recognize a unique set of self -peptides presented by the MHC Class Ib molecule Qa-1 differentially expressed on T cells as a function of the affinity / avidity of T cell acti vation.These Qa-1 restricted CD8 ~ + T cells represent an example of how the immune system utilizes a unified mechanism to regulate adaptive immunity to both self and foreign antigens. Thus, by selectively down-regulating T cells of intermediate affinity / avidity, to any antigens, the immune system controls the adaptive immunity without the necessity to distinguish self from non-self in the periphery at the level of T cell regulation. Cellular & Molecular Immunology. 2005; 2 (3): 161-167.