The failure to control HIV-1 infection results in immunodeficiency and destruction of the immune system in infected individuals. In addition to infecting and killing CD4+ T cells directly, HIV-1 causes chronic immune activation, which has been proposed to contribute to the immunodeficiency. Now, Rene van Lier's group have shown that persistent immune activation — in this study induced by chronic co-stimulation through CD27–CD70 interactions — can indeed result in lethal immunodeficiency.

Members of the tumour-necrosis factor receptor family, which includes CD27, are involved in the regulation of diverse immunological processes, including immune-cell proliferation and survival. CD70, the ligand for CD27, is expressed by activated lymphocytes after antigenic stimulation. Here, the authors used Cd70-transgenic mice, in which B cells chronically express CD70, as a model to assess the effects of persistent immune activation on the immune system.

Cd70-transgenic mice had increased numbers of effector T cells in their spleens and peripheral lymph nodes, owing to increased T-cell proliferation. With time, the number of naive T cells in the secondary lymphoid organs decreased, as did naive T-cell production, but effector-memory T cells accumulated. Further experiments showed that this excessive production of effector-memory T cells was dependent on CD27–CD70 interactions and on the presence of foreign antigens, but was independent of interferon-γ.

How do these changes in T-cell populations affect the health of the Cd70-transgenic mice? By 20 weeks of age, most of the mice suffered from Pneumocystis carinii pneumonia — an opportunistic infection that is commonly seen in situations of severe T-cell immunodeficiency — which resulted in their premature death at around 28 weeks of age.

This study shows that persistent immune activation, as has been proposed to occur during chronic HIV-1 infection, is sufficient to cause lethal immunodeficiency. As activated T cells from HIV-1-infected individuals have been shown to express increased levels of CD70, the authors suggest that CD27–CD70 interactions could be targeted to avoid the negative effects of persistent immune activation.