Dead or alive

B234/068 Col TEM of MRSA: resistant Staphylococcus bacteria CREDIT: DR KARI LOUNATMAA/SCIENCE PHOTO LIBRARY

Live vaccines usually give much better protection from infection than subunit vaccines or those based on preparations of dead or replication-defective microbes — but what is the immunological basis of this phenomenon? Increased antigen dose, altered antigen presentation and the nonspecific effects of inflammation are all possible mechanisms. Now, Gregoire Lauvau and co-workers, reporting in Science, have compared how live and killed vaccines interface with the immune system, using Listeria monocytogenes infection of mice as a model.

Although immunization with live L. monocytogenes induces long-lasting, CD8⁺ T-cell-dependent protective immunity, vaccination with heat-killed L. monocytogenes (HKLM) is ineffective. To find out why, the authors tracked CD8⁺ L. monocytogenes-specific T cells using MHC tetramers. They found that mice primed with live bacteria and HKLM-primed mice form recall CD8⁺ T-cell responses of equivalent magnitude.

Why, then, does this CD8⁺ T-cell memory response fail to protect HKLM-primed mice? One possible explanation is that CD4⁺ T-cell memory, which is not elicited by HKLM vaccination, is crucial for protection. To test this, CIITA ^−/− mice (which are CD4⁺ T-cell deficient) were immunized and challenged with live L. monocytogenes. These mice were immune to infection and their CD8⁺ T-cell recall responses were indistinguishable from those of wild-type mice, indicating that protective immunity does not depend on CD4⁺ T-cell memory.

The authors then took a closer look at the effects of live and HKLM vaccination on CD8⁺ T-cell priming. Naive CD8⁺ T cells from L. monocytogenes-specific TCR transgenic mice were transferred into an adoptive host which was then immunized. After immunization with live bacteria, the transgenic CD8⁺ T cells were found to undergo expansion, develop cytotoxic activity, and downregulate the resting-cell marker CD62L. Conversely, following immunization with HKLM, specific CD8⁺ T cells undergo fewer divisions, do not become cytotoxic, and remain CD62L^hi. This indicates that although HKLM vaccination leads to CD8⁺ T-cell memory, effector T cells — which are crucial for protective immunity — do not develop.

It is likely that this defect in effector cell generation is due to suboptimal antigen presentation, but at what level? When mice were primed with live bacteria and HKLM at the same time, two subsets of CD8⁺ T cells appeared — CD62L^hi and CD62L^lo. This shows that nonspecific inflammatory signals, released by infection with live bacteria, cannot rescue the defective antigen presentation of HKLM. Furthermore, live infection and HKLM might target distinct subsets of antigen-presenting cells.