The role of regulatory T cells in alloantigen tolerance

The diversification mechanism used by the adaptive immune system to maximize the recognition of foreign antigens has the side effect of generating autoreactivity. This effect is counteracted by deletion of cells expressing receptors with high affinity to self (central tolerance) and suppression of autoreactive cells by regulatory T cells (Tregs; peripheral tolerance). This understanding led to the notion that Tregs represent a specialized subset of autoreactive T cells with inhibitory function. The process of generating a diverse repertoire of receptors recognizing antigen presented by major histocompatibility complex (MHC) intrinsically leads to the generation of cells recognizing foreign MHC (alloantigen). The precursor frequency of T cells responding to alloantigen is substantially higher than that responding to any exogenous antigen. The only physiological context in which this becomes a problem is placental viviparity. Although the maternal immune system has no intrinsic mechanism to distinguish between a pathogen and paternally derived fetal alloantigen, it has to neutralize the former and tolerate the latter. We review the function of Tregs from this perspective and propose that they may have evolved to promote tolerance to alloantigen in the context of pregnancy.