How the Immune System Walks Memory Lane

The mammalian immune system has the memory of an elephant: If it encounters an invader it has fought off before, it responds with a much more vigorous attack. In this month's issue of Nature Immunology, researchers present findings that help explain this reaction: The first confrontation turns single-minded, laid-back "naïve" T cells into versatile, ultrafast combat squads of memory cells.

When the immune system stumbles upon an unknown foreign invader for the first time, it often takes days before lashing out with full force--a time during which T cells start dividing and differentiating into specialized cells, such as antibody-producing B cells and killer T cells. When the battle is won, a few of these cells turn into long-lived memory T cells, causing the response to be much swifter the next time around. One theory holds that this rapid reaction is simply a question of numbers: There are more T cells in the bloodstream primed to recognize a particular pathogen. But Henrique Veiga-Fernandes and his colleagues at the Institut Necker in Paris explored whether it may also be a question of conditioning: Battle-hardened memory T cells may respond differently from their rookie cousins.

The team set out to compare the immune response of naïve and memory T cells geared toward the same foe in mice. But that posed technical difficulties: Because the number of naïve T cells against any given antigen is too low to measure, they had to resort to a transgenic mouse that produces only a single type of T cell, directed against a protein called H-Y, which sits on the surface of all cells in male mice.

The team harvested both naïve and memory T cells against H-Y and injected them into mice from another strain that lacked B and T cells altogether; then they injected H-Y-studded male cells to provoke an immune reaction. They found that the memory T cells started dividing about 15 hours earlier than the naïve T cells; the memory cells were also quicker to start churning out immune hormones such as cytokines, which activate other immune cells. Such a head start "can be the difference between life and death," says Veiga-Fernandes. The memory T cells were also better at juggling tasks: Whereas individual naïve T cells produced only one specific cytokine, each memory cell churned out a number of them, in amounts up to 50 times higher.

The study "is the clearest demonstration yet that memory T cells respond quite differently," says David Gray of the University of Edinburgh in the U.K. But he cautions that the study's experimental conditions were quite artificial. Says Gray: "Studying immune cells in immunocompromised animals tells you what the cells can do, but not necessarily what they will do in a completely functional immune system."