The Role of Regulatory T Cells during Feline Immunodeficiency Virus Pathogenesis

Abstract

Human immunodeficiency virus-1 (HIV-1), simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV) are members of the Retroviridae family in the Lentivirinae genus. Lentiviral pathogenesis involves a prolonged period of immune dysregulation that eventually results in acquired immunodeficiency syndrome (AIDS). Data exploring the roles of CD4+ T helper cells, cytotoxic T lymphocytes, B cells, natural killer cells, and dendritic cells during acute simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV) infection suggest that mismanagement of the immune response begins early after lentiviral infection. Many studies suggest that CD4+CD25hiFOXP3+ immunosuppressive regulatory T (Treg) cells are involved in regulation of the immune response during HIV-1 and SIV infection and could be involved in modulating immune dysregulation. Treg cells can suppress lentiviral-specific immune responses, and therefore may play a detrimental role during infection. However, several studies point to a protective role of Treg cells in lentiviral infection, as high PBMC Treg cell frequencies are correlated with high CD4+ T cell counts, low T cell activation, and/or low viremia. Treg cells have been described in the cat, and their immunosuppressive capabilities have been shown to be enhanced during FIV infection. Therefore, we sought to (1) validate a method of in vivo Treg cell depletion via anti-CD25 monoclonal antibody (mAb) in the cat, (2) determine the role of Treg cells during chronic FIV pathogenesis by depleting Treg cells in cats chronically infected with FIV, and (3) determine whether Treg cells play a role in acute FIV pathogenesis by depleting Treg cells prior to infection. We found that anti-CD25 mAb administration in FIV naïve cats immunized with recombinant FIV p24 resulted in an 82% decrease in circulating CD4+CD25hi Treg cells at the nadir of depletion. Treg cells and FOXP3 mRNA were reduced in the thymus, secondary lymphoid tissues, and the gut up to day 35 post-depletion. Anti-CD25 mAb treatment did not disturb anti-FIV p24 cellular and humoral immune responses. Anti-CD25 mAb treatment in cats chronically infected with FIV revealed significant FIV-specific immune responses as measured by interferon (IFN)-γ production. Cats that received the Treg cell-depleting mAb were able to produce a significantly more robust humoral response to new antigen as compared to cats receiving an isotype control mAb. Importantly, transient Treg cell depletion in cats chronically infected with FIV did not induce damaging proinflammatory cytokine production or viral replication. Treg cell depletion prior to FIV infection did not significantly alter acute FIV pathogenesis. The effects of anti-CD25 mAb treatment appeared to be truncated in cats acutely infected with FIV as compared to chronically infected cats or FIV naïve cats, as Treg cell levels were heightened in all treatment groups after FIV infection. Therefore, we propose that the influence of Treg cell suppression during FIV pathogenesis is most prominent after established infection, when Treg cells are activated and more functionally suppressive. Our findings suggest that short-term in vivo Treg cell depletion during chronic lentiviral infection could provide a window of opportunity for therapeutic vaccination in individuals with controlled viral replication.