Tesselaar K, Arens R, van Scijndel GMW, et al. Nat Immunol. 2003;4:49–54
Purpose of the Study.
During human immunodeficiency virus (HIV) infection, CD4+ T cell levels decline. Studies suggested that this loss is less likely related to direct infection and killing of these cells than to exhaustion of the T cell pool induced by chronic immune activation. The purpose of this study was to determine, in an animal model, whether artificially induced chronic immune activation alone could result in clinically significant T cell deficiency.
Activation of T cells requires stimulation of the antigen-specific T-cell receptor and ligation of coreceptors on the T cell surface. One coreceptor on the surface of T cells is CD27, a member of the tumor necrosis factor receptor family. CD70 is the ligand for CD27. The investigators generated a CD70-transgenic mouse model in which CD70 was constitutively expressed on B cells, resulting in chronic T cell activation in the absence of viral infection.
These mice demonstrated progressive conversion of naïfive T cells into effector-memory cells. The end result was depletion of naı̈ve T cells from lymph nodes and spleen. Despite this hyperactive immune response, CD70-transgenic mice died as a result of Pneumocystis carinii pneumonia, which is an acquired immunodeficiency syndrome-defining condition among human patients infected with HIV.
Constant activation of T cells via CD27-CD70 interactions, as may occur among human subjects during chronic active viral infections, may result in exhaustion of the T cell pool and the development of fatal immunodeficiency.
It has been unclear how T cell loss occurs during HIV infection. Some T cells are undoubtedly killed by infection with HIV. However, the magnitude of the T cell loss is not explained by this pathway. Very early in the HIV epidemic, it appeared that chronic immune activation was a hallmark of HIV disease. Was the immune activation a cause of T cell loss or simply the effect of chronic viral infection? In other primates, chronic infection with retroviruses may not cause any detectable immune dysfunction if immune activation is not induced. This study clearly demonstrated that immune activation alone might be sufficient to induce T cell deficiency. If the virus cannot be eradicated, then perhaps induction of immunologic tolerance to it may be the next best thing.