Even with the two-signal requirement, some self-reactive lymphocytes escape into the periphery. Peripheral tolerance is the set of mechanisms that restrain them there. Regulatory T cells, marked by the transcription factor FoxP3, suppress the activation and effector function of self-reactive conventional T cells through contact-dependent inhibition and the secretion of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta. Inhibitory receptors on the surface of activated T cells, including CTLA-4 and PD-1, raise the threshold for further activation. CTLA-4 competes with CD28 for CD80 and CD86, removing the costimulatory signal, while PD-1 recruits phosphatases that dampen the T cell receptor signal. Together these mechanisms ensure that a lymphocyte encountering self-antigen in the periphery is more likely to be suppressed than activated.
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Regulatory T cells, marked by FoxP3, suppress self-reactive conventional T cells through direct contact and by secreting interleukin-10 and transforming growth factor beta. Inhibitory receptors work differently. CTLA-4 competes with CD28 for the same costimulatory ligands, so it removes signal two. PD-1 recruits phosphatases that weaken the T cell receptor signal. Both mechanisms raise the threshold a self-reactive lymphocyte must cross before it can cause damage. Peripheral tolerance is not a single barrier; it is several overlapping restraints.
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