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.
References
ORIGINAL RESEARCH PAPER
Kreuwel, T. C., Aung, S., Silao, C. & Sherman, A. Memory CD8+ T cells undergo peripheral tolerance. Immunity 17, 73–81 (2002)
FURTHER READING
Cho, B. K., Wang, C., Sugawa, S., Eisen, H. E. & Chen, J. Functional differences between memory and naive CD8 T cells. Proc. Natl Acad. Sci. USA 96, 2976–2981
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Minton, K. Losing your memory. Nat Rev Immunol 2, 630 (2002). https://doi.org/10.1038/nri892
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DOI: https://doi.org/10.1038/nri892