Many studies have shown that the ectopic expression of a self-antigen in pancreatic β-cells results in cross-presentation on MHC class I molecules to naive CD8+ T cells in the draining lymph nodes. The resulting 'cross-tolerance' is one mechanism by which peripheral tolerance to self-antigens is maintained. However, Kreuwel et al. have now found that this phenomenon is not restricted to naive T cells. They suggest that memory CD8+ T cells are as susceptible to tolerance as are naive cells. This 'second chance' at peripheral tolerance might explain how autoimmunity is avoided even if naive autoreactive T cells that have not yet been tolerized become activated.

InsHA mice — which express influenza-virus haemagglutinin (HA) under the control of the rat insulin (Ins) promoter — are tolerant of HA even after immunization with influenza virus. However, cross-presentation does not occur in neonatal mice, which develop diabetes after immunization. But, those neonates that survive gradually recover as cross-presentation of islet antigens develops. The authors show that the responses of HA-specific memory CD8+ T cells that are present three weeks after immunization of neonates are severely diminished by 11 weeks. When naive and memory CD8+ Clone-4 T-cell receptor cells (which are specific for a dominant epitope of HA) were injected into InsHA recipients, both cell types proliferated to a similar extent in an antigen-specific manner. In both cases, the T cells did not increase in number despite division, which indicates that they were tolerized by deletion. The rate of tolerance induction is greater in InsHA+/+ mice than in InsHA+/− mice, which indicates that clonal deletion is the result of HA, rather than normal T-cell turnover, and that the rate of deletion is determined by the concentration of antigen that is available for cross-presentation.

This work questions the assumption that naive T cells are fundamentally different to memory T cells with respect to tolerance susceptibility. It also has implications for the development of tumour vaccines. If memory T cells are routinely tolerized to cross-presented antigens, it might not be possible to sustain long-lived T-cell immunity to tumour antigens, which are often also expressed on non-transformed tissues.