Th17 and IL-17 play important roles in the clearance of extracellular bacterial and fungal infections. However, strong evidence also implicates the Th17 lineage in several autoimmune disorders including multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and asthma. The Th17 subset has also been connected with type I diabetes, although whether it plays a role in the pathogenicity of or protection from the disease remains a controversial issue. In this review we have provided a comprehensive overview of Th17 pathogenicity and function, including novel evidence for a protective role of Th17 cells in conjunction with the microbiota gut flora in T1D onset and progression.
Th17 cells are a distinct subset of T cells that have been found to produce interleukin 17 , and differ in function from the other T cell subsets including Th1, Th2, and regulatory T cells. Th17 cells have emerged as a central culprit in overzealous inflammatory immune responses associated with many autoimmune disorders. In this method we purify T lymphocytes from the spleen and lymph nodes of C57BL/6 mice, and stimulate purified CD4+ T cells under control and Th17-inducing environments. The Th17-inducing environment includes stimulation in the presence of anti-CD3 and anti-CD28 antibodies, IL-6, and TGF-β. After incubation for at least 72 hours and for up to five days at 37 °C, cells are subsequently analyzed for the capability to produce IL-17 through flow cytometry, qPCR, and ELISAs. Th17 differentiated CD4+CD25-T cells can be utilized to further elucidate the role that Th17 cells play in the onset and progression of autoimmunity and host defense. Moreover, Th17 differentiation of CD4+CD25-lymphocytes from distinct murine knockout/disease models can contribute to our understanding of cell fate plasticity. Video LinkThe video component of this article can be found at
We have developed an antagonist to suppressor of cytokine signaling 1 (SOCS1), pJAK2(1001–1013), which corresponds to the activation loop of the Janus kinase JAK2, which is the binding site for the kinase inhibitory region (KIR) of SOCS1. Internalized pJAK2(1001–1013) inhibits SOCS1 and SOCS3. SOCS1 has been shown to be an influenza virus-induced virulence factor that enhances infection of cells. The antagonist was protective in cell culture and in influenza virus PR8 lethally infected C57BL/6 mice. The SOCS antagonist also prevented adverse morbidity as assessed by parameters, such as weight loss and drop in body temperature, and showed potent induction of both the cellular and humoral immune responses to the influenza virus candidate universal antigen matrix protein 2 (M2e). The SOCS antagonist, thus, protected mice against lethal influenza virus infection and possessed potent adjuvancy against the M2e candidate influenza virus universal vaccine antigen.
The intracellular protein Suppressors of Cytokine Signaling1 (SOCS1) plays a critical role in moderating inflammatory cytokine signaling, thereby limiting immune responsiveness. We have shown that a peptide with the kinase inhibitory region of SOCS1 (SOCS1-KIR) inhibits Experimental Autoimmune Encephalomyelitis and rescues SOCS1-deficient mice from perinatal lethality. In contrast, a SOCS1antagonist pJAK2 enhances antiviral immunity to poxviruses. Therefore it is likely that peptides that modulate SOCS1 signaling possess the potential to modulate immune responses, and restore immune homeostasis. To evaluate the translational potential of SOCS1 mimetic peptides, we have assessed their pharmacodynamics by fluorescently labeling the peptides followed by injection into C57BL/6 mice. After 2 hours mice receiving Alexa 647 fluorochrome-conjugated SOCS1-KIR or pJAK2 were sacrificed, and subsequently whole organs and tissue histology were examined for the presence of the labeled peptides. We observed that pJAK2 and SOCS1-KIR were present in the brain, liver, lymph nodes, spleen, kidneys, lungs, and peritoneal cells. Notably, pJAK2 was selectively present within the thymus and heart. On a cellular level, SOCS1-KIR and pJAK2 were differentially present within CD4+ T cells, CD8+ T cells, CD11b+ macrophages, and B cells. These results help to lay the groundwork for the translational use of peptides that modulate SOCS signaling to regulate and/or maintain immune system homeostasis.
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