Chemokine and Cytokine Mediated Loss of Regulatory T Cells in Lymph Nodes during Pathogenic Simian Immunodeficiency Virus Infection

Abstract

Regulatory T cells (Treg) play key roles in immune regulation through multiple modes of suppression. The effects of HIV-1 infection on Treg levels in lymphoid tissues remain incompletely understood. To explore this issue, we have measured the levels of forkhead box protein 3 (FOXP3)-positive cells and associated immunomodulatory genes in a pathogenic simian immunodeficiency virus/macaque model and found that a loss of Treg in lymph nodes occurred following simian immunodeficiency virus infection. Changes in expression of the ligands for CXCR3, CCR4, and CCR7 and the cytokines TGF-β and IL-2 were all linked to this loss of Treg, which in turn was linked with increased levels of cellular activation. Our findings identify three mechanisms that likely contribute to SIV-driven loss of Treg, including reduced levels of cytokines associated with Treg differentiation and altered expression of agonist and antagonist chemokines. The loss of Treg and the associated cellular activation in lymphoid tissues is consistent with the events in HIV-1-infected individuals and suggest that components of the Treg differentiation and trafficking network could be targets for therapeutic intervention.