Date Published: March 6, 2014
Publisher: Public Library of Science
Author(s): Cecile Le Saout, Rebecca B. Hasley, Hiromi Imamichi, Lueng Tcheung, Zonghui Hu, Megan A. Luckey, Jung-Hyun Park, Scott K. Durum, Mindy Smith, Adam W. Rupert, Michael C. Sneller, H. Clifford Lane, Marta Catalfamo, Guido Silvestri.
HIV infection and the associated chronic immune activation alter T cell homeostasis leading to CD4 T cell depletion and CD8 T cell expansion. The mechanisms behind these outcomes are not totally defined and only partially explained by the direct cytopathic effect of the virus. In this manuscript, we addressed the impact of lymphopenia and chronic exposure to IFN-α on T cell homeostasis. In a lymphopenic murine model, this interaction led to decreased CD4 counts and CD8 T cell expansion in association with an increase in the Signal Transducer and Activator of Transcription 1 (STAT1) levels resulting in enhanced CD4 T cell responsiveness to IFN-α. Thus, in the setting of HIV infection, chronic stimulation of this pathway could be detrimental for CD4 T cell homeostasis.
Homeostatic forces regulate the number and survival of T cell clones throughout life, allowing only a limited degree of non-antigen driven expansion for each individual cell in order to preserve the diversity of the T cell repertoire . This is achieved by a balance between signals that mediate survival and proliferation, which are regulated by homeostatic cytokines such as IL-7 and IL-15. Through homeostatic mechanisms, the size of the T cell pool remains relatively constant despite the expansion of T cell clones during antigen-specific responses. In an immune competent host, homeostatic proliferation is controlled by the limited availability of homeostatic cytokines. However, under lymphopenic conditions, a robust homeostatic proliferation occurs leading to polyclonal T cell expansion and accumulation of cells with a highly activated memory phenotype . This is observed in certain human clinical conditions such as bone marrow transplants and HIV infection, where an increased availability of IL-7 is detected in the serum of the patients –. During HIV infection, in addition to HIV-specific immune responses, there is a generalized immune activation that alters the homeostasis of the CD4 and CD8 T cell pools leading to CD4 T cell depletion and CD8 T cell expansion. The mechanisms behind these extreme outcomes are not totally understood. The direct cytopathic effects of HIV do not appear adequate to explain this dichotomy. HIV-induced CD4 T cell depletion triggers a homeostatic response that occurs in an inflammatory environment rich in Type-I IFNs and driven by HIV replication. Both lymphopenia and viral load contribute to the immune activation observed in the CD4 T cell pool. In contrast, the expansion and activation of the CD8 T cell pool is tightly correlated with levels of HIV replication and does not appear influenced by homeostatic forces –. The Type-I IFN activity associated with HIV infection is reflected by increased mRNA transcripts of genes such as OAS1, ISG15, IFNAR1 and STAT1 in both CD4 and CD8 T cells –.
Patients with HIV infection show a unique form of immune activation leading to CD4 T cell depletion and CD8 T cell expansion. The CD4 T cell depletion observed in these patients is only partially explained by a direct cytopathic effect of the virus. The small number of actively infected cells at any given point suggests that other mechanisms may play a role , . The mechanisms behind these extreme outcomes for both CD4 and CD8 T cells pools remain unresolved. Because CD4 T cells are under continuous homeostatic pressure, we hypothesized that these outcomes could be associated with differences in homeostatic regulation of these two pools and in their response to the combination of cytokines associated with lymphopenia and viral replication. In the present manuscript, we have shown that chronic exposure to Type-I IFN under lymphopenic conditions can lead to impaired CD4 T cell homeostasis resulting in diminished CD4 T cell counts in association with CD8 T cell expansion. This phenotype recapitulates the alterations of the CD4 and CD8 T cell pools seen in patients with HIV infection. Our data support a model in which CD4 T cells under lymphopenic conditions become more responsive to IFN-α by modulating the levels of STATs. This continuous stimulation of CD4 T cells may lead to activation induced cell death (AICD) and decreased survival. In contrast, the same set of stimuli lead to CD8 T cell expansion.