Abstract
Regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance, preventing autoimmune diseases and restraining chronic inflammatory diseases. Evidence suggests Treg cells and NK cells have important roles in feline immunodeficiency virus (FIV) pathogenesis; however, in vivo studies investigating the interplay between these two cell populations are lacking. We previously described innate immune defects in FIV-infected cats characterized by cytokine deficits and impaired natural killer cell (NK) and NK T cell (NKT) functions. In this study, we investigated whether in vivo Treg depletion by treatment with an anti-feline CD25 monoclonal antibody would improve the innate immune response against subcutaneous challenge with Listeria monocytogenes (Lm). Treg depletion resulted in an increased overall number of cells in Lm-draining lymph nodes and increased proliferation of NK and NKT cells in FIV-infected cats. Treg depletion did not normalize expression of perforin or granzyme A by NK and NKT cells, nor did Treg depletion result in improved clearance of Lm. Thus, despite the quantitative improvements in the NK and NKT cell responses to Lm, there was no functional improvement in the early control of Lm. CD1a+ dendritic cell percentages in the lymph nodes of FIV-infected cats were lower than in specific-pathogen-free control cats and failed to upregulate CD80 even when Treg were depleted. Taken together, Treg depletion failed to improve the innate immune response of FIV-infected cats against Lm and this may be due to dendritic cell dysfunction.
Highlights
Three key immunological features of lentiviral infection are the lack of an effective immune response against the virus, susceptibility to opportunistic pathogens, and generalized immune activation.The underlying mechanisms that lead to these immunologic alterations are complex and interrelated.Regulatory T cells (Treg) are thought to contribute to the control of excessive immune activation on one hand and suppression of the anti-viral response on the other hand [1]
We showed that locally delivered interleukin 15 (IL-15), a cytokine known to activate and stimulate natural killer (NK) cells, significantly restored innate immune function as measured by Listeria monocytogenes (Lm) clearance [9]
feline immunodeficiency virus (FIV) infection leads to increased apoptosis of lymphocytes, as determined by Annexin V expression in an increased proliferation of NK cells and NK T cell (NKT) cells in response to Lm challenge, rendering a in both control LN (CLN) and Lm-lymph nodes (LN) when compared to SPF-control cats [10]
Summary
Three key immunological features of lentiviral infection are the lack of an effective immune response against the virus, susceptibility to opportunistic pathogens, and generalized immune activation. We have employed the intracellular opportunistic pathogen Listeria monocytogenes (Lm) to probe the immune defects associated with FIV Using this immune challenge model, we found that FIV-infected cats have an impaired innate response that fails to gain initial control of bacterial replication prior to the adaptive immune response [8]. Our objective in the present study was to determine whether Treg contribute to the impaired NK cell function in FIV-infected cats, and reduced capacity to clear Lm. We hypothesized that in vivo Treg cell depletion using anti-feline CD25 monoclonal antibody prior to innate immune challenge with Lm would improve the innate immune response and the clearance of bacteria
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