Role of the serine-threonine kinase Tpl2 in Th17 responses in infectious and autoimmune diseases
Acuff, Nicole Vivienne
MetadataShow full item record
Tpl2 is a serine threonine kinase that regulates inflammatory pathways of the immune system. Small molecule inhibitors of Tpl2 are being developed as possible therapeutics for autoimmune diseases in which Th1 and Th17 cells contribute to pathology. A more complete understanding of how Tpl2 regulates Th17 responses during autoimmune and infectious diseases may provide valuable information about the potential benefits versus risks associated with Tpl2 inhibition. We show that Tpl2 promotes Th17 differentiation and effector functions at several stages. In vitro, IL-17A expression by Tpl2-/- CD4 T cells was dependent upon TGF-β and inhibited by FoxP3 expression. In a T cell transfer model of colitis, Tpl2-/- CD4 T cells were capable of differentiating into Th17 cells expressing IL-17A, but were impaired in Th1 differentiation and IFNγ production. Tpl2-/- CD4 T cells also showed enhanced lymphopenia-induced proliferation, which compensated for reduced IFNγ in driving similar overall pathology scores. A Tpl2-dependent role for CD4 T cell differentiation into Th1 and Th17 cells expressing IFNγ and IL-17A was observed in Tpl2-/- mice infected with Citrobacter rodentium, although adoptive transfer of CD4 T cells into Rag1-/- mice prior to infection confirmed that the T cell defect was not responsible for increased bacterial burdens observed in Tpl2-/- mice. Despite enhanced bacterial burdens, Tpl2-/- mice experienced reduced pathology and inflammatory neutrophil infiltrate into the intestines during C. rodentium infection. Neutrophil egress from the bone marrow during homeostasis and inflammation-induced neutrophil recruitment from the blood to inflammatory sites was reduced in Tpl2-/- mice due to neutrophil-extrinsic defects in inflammatory chemokine and cytokine production. Furthermore, Tpl2-/- neutrophils showed impaired antimicrobial functions, including cytokine secretion and superoxide production, compared to wild type neutrophils. Consequently, Tpl2-/- and Rag1-/-Tpl2-/- mice developed greater bacterial burdens and disseminated infection to the Gram-negative and Gram-positive extracellular bacteria, Citrobacter rodentium and Staphylococcus xylosus. Overall, the role for Tpl2 in driving an inflammatory response was model-specific, confirming a cell-type and stimulus-specific role for Tpl2. These data suggest that Tpl2 inhibitors would be beneficial in preventing inflammatory cell infiltrates and immune pathology during autoimmunity but caution that chronic administration may predispose patients to extracellular bacterial infections.