Browsing by Subject "IL-17A"
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Item Characterization of IL-17A-Secreting CD8 T Cells(2008-12-01) Lee, Suheung; Harlan Jones; Porunellor Mathew; Peter KoulenIL-17A-secreting CD4 T cells (Th17 cells) have been demonstrated to play pivotal roles in modulating immune responses during various types to infectious and autoimmune diseases. While 1L-17A secreting CD8 T cells have been detected in numerous disease models, much less is known about them. In this thesis, the differentiation conditions and effector functions of IL-17A-secreting CD8 T cells have been examined. In order to differentiate naïve CD8 T cells into IL-17A secretors, TGF-β, IL-6, and neutralization of IFN-γ are required as in Th17 cells. IL-17A-secreting CD8 T cells produce the effector cytokines, IL-17A, IL-17F and IL-22, but do not produce granzyme B, implicating the lack of cytotoxicity. Furthermore, IL-17A-secreting CD8 T cells can respond to exogenous cytokines without a cognate antigen, suggesting that they can act in an innate fashion. Collectively, IL-17A-secreting CD8 T cells possess the same effector functions as Th17 cells, and thus may play as significant roles in various diseases at Th17 cells.Item Interleukin-17A (IL-17A) worsens severe murine respiratory mycoplasma disease(2018-08-01) Mize, Maximillion; Jerry W. Simecka; Rance E. Berg; Harlan P. JonesThe purpose of these studies was to determine the role of Interleukin-17A (IL-17A) in the immune response to respiratory mycoplasma infection. Serum levels of IL-17A increase in disease-susceptible BALB/c mice, but not disease-resistant C57BL/6 mice, infected with Mycoplasma pulmonis. Increased serum IL-17A was associated with mycoplasma pathology during infection in BALB/c mice, including: the presence of pulmonary neutrophils, progressive weight loss, and the development of inflammatory lung lesions. Neutralizing the function of IL-17A using monoclonal anti-IL-17A antibodies during mycoplasma infection reduced disease severity in disease-susceptible BALB/c mice, but not disease-resistant C57BL/6 mice. Providing daily intra-peritoneal injections of anti-IL-17A antibodies to BALB/c mice infected with M. pulmonis was effective at reducing weight loss, the prevalence of clinical signs, and the incidence of gross lesions. Histological lesions, characterized by the presence of pulmonary neutrophils, were also lower in infected BALB/c mice receiving anti-IL-17A antibodies daily. Bacterial burden remained unaffected in mice regardless of treatment. Neutralizing IL-17A throughout infection was effective at reducing late mycoplasma pathology, a period influenced by the actions of adaptive immunity and this is supported by a reduction in disease severity when infected BALB/c mice were provided intra-peritoneal injections of anti-IL-17A antibodies only after T-cells infiltrate the lungs. Pulmonary T-cells, specifically CD4+ T-helper (Th17) cells, were the primary source of IL-17A throughout infection with M. pulmonis in disease-susceptible BALB/c mice. Although Th17 cells increased in the lung after infection, the Th17 response did not reach its peak until the later stages of infection and coincided with when the neutralization of IL-17A started to reduce the severity of disease. IL-17A+ T-cells did not express Retinoic Acid Related (RAR) Orphan Receptor-γt (RORγt), a signature Th17 transcription factor, after infecting BALB/c mice with M. pulmonis and suggests that RORγt is not a suitable marker to identify the IL-17A+ T-cells worsening mycoplasma disease. The effect of neutralizing IL-17A was mimicked in disease-susceptible BALB/c mice depleted of neutrophils during M. pulmonis infection. Depleting neutrophils in BALB/c mice infected with M. pulmonis abrogated weight loss while reducing the appearance of both clinical signs and gross lesions. IL-17A promotes pathology during disease utilizing various mechanisms, one of which is to mobilize and activate neutrophils; however, the IL-17A failed to worsen mycoplasma disease in the absence of neutrophils during M. pulmonis infection in BALB/c mice. These results suggest that IL-17A relies only upon neutrophil recruitment and activation to exacerbate mycoplasma disease. Supporting this, combining the neutralization of IL-17A with the depletion of neutrophils failed to lessen disease severity beyond what either treatment could achieve alone. These findings underscore IL-17A or neutrophils as targets for inhibition to reduce the severity of disease during mycoplasma infection. Both IL-4 and IL-17A increase in the lungs of BALB/c mice infected with M. pulmonis and there are Th17 cells that secrete IL-4. In STAT6 KO mice that respond poorly to IL-4 and generate defective Th2-mediate immunity, neutralizing IL-17A also reduced inflammatory damage during M. pulmonis infection. Treating STAT6 KO mice with anti-IL-17A antibodies during M. pulmonis infection reduced weight loss, the prevalence of clinical signs, and incidence of inflammatory lesions. Like wild-type mice, the pathologic effect of IL-17A manifested during the later stages of M. pulmonis infection in STAT6 KO mice and coincided with the activation of adaptive immunity. Neutralizing IL-17A also failed to change mycoplasma numbers during infection in STAT6 KO mice. IL-17A is highlighted as an independent contributor to mycoplasma pathology with no impact on mycoplasma clearance; inhibiting the activation of Th2- and Th17-mediated immune responses could increase resistance by permitting the development of protective responses during infection. This work emphasizes the importance of IL-17A and Th17 cells as an autonomous immune response worsening neutrophil-mediated pathology during late mycoplasma infection in susceptible mice. Monoclonal antibodies that neutralize the function of IL-17A could reduce the severity of disease during mycoplasma infection in man and animals. Directly targeting neutrophils may also lessen the negative impact IL-17A has on mycoplasma pathology. Vaccines that do not activate IL-17A-mediated immunity could reduce the susceptibility to mycoplasma infection and allow for the development of immune responses that lead to mycoplasma clearance. IL-17A functions to worsen disease severity without impacting mycoplasma clearance, and so IL-17A is identified as a contributor to pathology during infection.