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Abstract
Inflammation is critical for host protection against intracellular pathogens. Shortly after an intracellular infection, antigen-presenting cells produce IL-12 to promote CD4+ T cell differentiation into TH1 CD4+ T cells that contribute to pathogen clearance by IFNγ production. However, TH1-driven inflammation must be regulated because excessive inflammation can result in autoimmune diseases such as inflammatory bowel disease. Even though there are several drug therapies available to limit inflammation caused by TH1-driven autoimmunity, many leave hosts vulnerable to intracellular infections by dramatically suppressing their TH1-immune response. Before we can design novel therapeutics aimed to treat TH1-associated autoimmunity with limited side effects, we need a better understanding of the regulatory pathways involved in this inflammatory response. In these studies, we find that the protein placenta-specific 8 (Plac8) is highly expressed within TH1 CD4+ T cells differentiated in vitro and may contribute to TH1-driven inflammation. In addition to CD4+ T cells, we show that Plac8 is expressed at very high basal levels in CD8+ T cells and is further induced following IL-12 stimulation. Interestingly, Plac8 suppresses IFNγ production by CD4+ and CD8+ T cells following IL-12 stimulation in vitro which suggests Plac8 could suppress TH1-driven inflammation. Although Plac8 does not significantly regulate IFNγ production by pathogenic CD4+ T cells during a T cell transfer model of colitis, we observe that Plac8 promotes optimal establishment of antigen-specific CD8+ T cells following influenza infection. Furthermore, we find that Plac8 is important for limiting Citrobacter rodentium bacterial burdens as early as 3 days post infection. Although Plac8 ablation did not directly alter the ability of neutrophils to kill C. rodentium in vitro, we find that Plac8 expression may promote colonic CXCL1 production in C. rodentium-infected mice. Therefore, the contribution of Plac8 during C. rodentium infection may be to limit bacterial burdens by upregulating colonic expression of CXCL1 and increasing neutrophil recruitment to the site of infection. Although the precise function of Plac8 during these inflammatory responses remains elusive, for the first time, these data show that Plac8 has an immunoregulatory role during TH1 immune responses and should be further explored for potential therapeutic benefit.