CD4 and CD8 T Cell Immune Activation during Chronic HIV Infection: Roles of Homeostasis, HIV, Type I IFN, and IL-7

Abstract

Immune activation plays an important role in the pathogenesis of HIV disease. Although the causes are not fully understood, the forces that lead to immune dysfunction differ for CD4 and CD8 T cells. In this study, we report that the molecular pathways that drive immune activation during chronic HIV infection are influenced by differences in the homeostatic regulation of the CD4 and CD8 T cell pools. Proliferation of CD4 T cells is controlled more tightly by CD4 T cell numbers than is CD8 T cell proliferation. This difference reflects the importance of maintaining a polyclonal CD4 T cell pool in host surveillance. Both pools of T cells were found to be driven by viral load and its associated state of inflammation. In the setting of HIV-induced lymphopenia, naive CD4 T cells were recruited mainly into the proliferating pool in response to CD4 T cell depletion, whereas naive CD8 T cell proliferation was driven mainly by levels of HIV RNA. RNA analysis revealed increased expression of genes associated with type I IFN and common γ chain cytokine signaling in CD4 T cell subsets and only type I IFN-associated genes in CD8 T cell subsets. In vitro studies demonstrated enhanced STAT1 phosphorylation in response to IFN-α and increased expression of the IFNAR1 transcripts in naive and memory CD4 T cells compared with that observed in CD8 T cells. CD4 T cell subsets also showed enhanced STAT1 phosphorylation in response to exogenous IL-7.

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

“…It is possible that influenza-specific T cells are activated in the context of HIV-1 infection because of cross-reactivity for HIV-1 peptides (51). Although such cross-reactivity might contribute, it would not readily explain the observation that adenovirus-specific CD8 + T cell responses are similarly affected and that overall levels of CD8 + T cell activation and proliferation correlate with HIV-1 viral load (42,43 T cells much faster than that of CD4 + T cells. So far the relevance of TCR-independent T cell activation, involving cytokine stimulation or engagement of pattern recognition receptors, in chronic HIV-1 infection is not known, but it is possible that the inflammatory environment present during untreated HIV-1 infection has a significant effect on the induction of T cell hyperactivation and consequently contributes to disease progression (8,11,27 + T cells and not CD4 + T cells, both with respect to upregulation of the activation markers CD38 and HLA-DR, which are commonly used to characterize activated T cells in HIV-1-infected patients and with respect to proliferation.…”

IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion

“…In patients with HIV infection, following combination antiretroviral therapy (cART), the CD4 + T cell reconstitution is slow and could take many years, depending on the CD4 + T cell number prior to initiation of therapy (17)(18)(19). Together, these observations suggest that CD4 + and CD8 + T cell pools are differentially regulated and these characteristics may be exploited by HIV, contributing to the dysregulation of the T cell pools observed in these patients (16,(20)(21)(22)(23)(24).…”

Severe Impairment of Regulatory T-Cells and Th1-Lymphocyte Polarization in Patients with Gaucher Disease

“…Impairment of T-helper cell function appears to be a constitutive feature of GD, since it is not affected by disease severity, effectiveness of treatment, previous splenectomy, or other features. Low CD4+ cell count is a hallmark of chronic inflammatory diseases, such as HIV infection (Catalfamo et al 2011) and chronic parasitic infestations (Kalinkovich et al 1998), and may result from an increased rate of apoptosis in the CD4+ cell compartment, something already described in chronic immune stimulationassociated diseases and conditions (Jelley-Gibbs et al 2005). …”