Understanding T-cell memory

Researchers report in the in the April 23 Science that the reason some T cells survive the T-cell die-off following infection clearance—and therefore provide long-term protection against infection—is the expression of a specific form of CD8.The work got its start in the mucosal lining of the intestine. “In a previous study… we discovered that a molecule, CD8aa, is expressed on the mucosal T cells but not on other T cells,” said Hilde Cheroutre of the La Jolla Institute for Allergy and Immunology and senior author of the study.T cells can express two CD8 molecules: CD8aß and CD8aa. According to Cheroutre, one control for this study was using T cells from the spleen because they do not normally express CD8aa. But to the group's surprise, spleen T cells transiently expressed CD8aa upon activation. “At first we were not so happy with this, but I decided to get to the bottom of it and try to understand what was going on,” Cheroutre told The Scientist.In this latest study, the team showed upon stimulation of CD8aa -negative spleen cells in vitro, these cells underwent apoptosis, but CD8aa -positive cells did not. As a follow-up, mice that express CD8aß, but do not express CD8aa (E81 knockout mice), were challenged with lymphocytic choriomeningitis virus and had considerably reduced numbers of antigen-specific memory T cells, confirming CD8aa's role in memory T-cell generation. “We discovered that those T cells that induce CD8aa during the primary activation are selected out by the immune system to survive the initial assault and to differentiate to memory T cells,” Cheroutre told The Scientist. “It also brought a lot of clarifications about the mysterious CD8aa molecule.” “There is certainly a lot of interest in the field to better understand when and how memory T cells are generated in vivo. The manuscript by Madakamutil et al. might have important implications for both aspects,” said Dirk Busch, from the Technical University of Munich, who was not involved in the study. “The results are very interesting,” said David Tough, from the Edward Jenner Institute for Vaccine Research. “From a basic immunology point of view, the results add to our understanding of how CD8 T-cell memory is generated,” Tough, who was not involved in the study, told The Scientist. “Apart from its academic interest in the field of immunology, an enhanced understanding of how immunological memory is generated may have practical implications for the design of improved vaccines through 'rational' approaches,” said Tough.But both Busch and Tough caution that questions still remain—for example, whether any secondary effects are present in the E81 knockout mice. “In addition, studying the response to other pathogens would be required to show that CD8aa has a general role in the generation of CD8 memory,” said Tough. “The amount of CD8aa -expressing T cells responding to the vaccine will reflect the size and effectiveness of the memory the patient will form against that particular pathogen,” said Cheroutre; therefore, “the ability to identify the memory precursor cells in a pool of responder T cells could provide significant help to screen for more effective vaccines.” “These findings are of substantial clinical importance, since it might make it possible to obtain information about the quality of long-term protective immunity early during an immune response. Furthermore, the ability to monitor the development of T-cell subsets early after immunization is likely to improve vaccine development,” Busch told The Scientist.

Understanding T-cell memory

Expression of a specific CD8 molecule enables the development of a memory T-cell pool

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