Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

Abstract

FoxP3 + CD4 + CD25 + regulatory T (Treg) cells are implicated in a number of pathologic processes including elevated levels in cancers and infectious diseases, and reduced levels in autoimmune diseases. Treg cells are activated to modulate immune responses to avoid over-reactive immunity. However, conflicting findings are reported regarding relative levels of Treg cells during HIV-1 infection and disease progression. The role of Treg cells in HIV-1 diseases (aberrant immune activation) is poorly understood due to lack of a robust model. We summarize here the regulation and function of Foxp3 in Treg cells and in modulating HIV-1 replication. Based on recent findings from SIV/monkey and HIV/humanized mouse models, a model of the dual role of Treg cells in HIV-1 infection and immuno-pathogenesis is discussed. KeywordsRegulatory T cells; AIDS; Chromatin; Epigenetic; Humanized mouse; DKO-hu; ONTAK Regulatory T cells play an important role in self immune tolerance and in balanced immune responsesThe regulation of immune tolerance is a critical aspect of immunology. The balance between recognition of self versus non-self is essential for maintenance of immune homeostasis. Regulatory T cells (CD4 + CD25 + ) are a crucial component for the control of deleterious effects from excessive immune responses as seen in autoimmune disease or allergic insult [1,2]. Treg cells have been implicated in a number of pathologic processes including elevated levels in cancers [3][4][5] and infectious diseases [6][7][8][9], and reduced levels in autoimmune diseases [1,[10][11][12][13]. It is apparent that Treg cells are induced (or recruited and expanded) by most infections to modulate host immune responses to avoid overreactive immunity (Fig. 1). As a result, Treg play a critical role in immune responses, vaccinations as well as in immunopathogenesis of pathogens. For example, Leishmania infection leads to induction of Treg that help to maintain the balance of immune response and pathogen persistence [18,19]. For the host, persistence of the pathogen is beneficial to maintain effective immunity against these pathogens [18]. In a number of chronic viral infections, Treg are induced to subdue the anti-viral immune responses and allow persistent infection. Mechanisms of CD4 T-cell differentiationT-cell lineage commitment and activation of T cells are usually accompanied by changes in patterns of gene expression. During T-cell responses, T helper (Th) progenitor cells will undergo Th1 or Th2 lineage commitments involving well-defined initiation cytokines, transcription factors, and effector cytokines. Expression of T-bet and GATA3 in Th1 and Th2 cells, respectively, is epigenetically regulated by histone modification and DNA methylation. As T lineage determinants, T-bet or GATA3 are also involved in epigenetically reprogramming the T-cell genome to silence the Th2 or Th1 effector cytokines, respectively, and to activate Th1 or Th2 cytokine genes for transcription (Fig. 2). Similarly, Th17 cell differentiation requires IL-6/TGF-β (mo...

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