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Browsing by Subject "autoimmunity"

Now showing 1 - 2 of 2
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    Programmed death-1 regulates islet-specific lymphocytes in type 1 diabetes
    (2018-12) Martinov, Tijana
    Programmed death-1 (PD-1) is a T cell inhibitory receptor important for tolerance maintenance. PD-1 is highly expressed on chronically stimulated T cells, such as those specific for persistent viral or tumor antigens. PD-1 pathway blockade revolutionized cancer therapy in recent years. While response rates are higher than with chemotherapy, not all patients respond, and some develop autoimmune-like symptoms, or even overt autoimmunity. Herein, I sought to understand how the PD-1 pathway regulated islet-specific CD4+ T cells during type 1 diabetes (T1D) progression in non-obese diabetic (NOD) mice. Since insulin itself is one of the main antigens driving T1D, we developed insulin peptide:MHCII tetramer reagents to track insulin-reactive CD4+ T cells. Insulin-specific CD4+ T cells that expressed the most PD-1 also had the highest affinity for self, suggesting that PD-1 preferentially regulated those cells with the highest autoimmune potential. In NOD mice, the majority of insulin-specific CD4+ T cells had an anergic (tolerant) phenotype, but surprisingly, PD-1 blockade did not override the anergy program. These findings suggested that the differentiation state of the CD4+ T cell pre-determine its susceptibility to PD-1 blockade. Autoantibody production is a hallmark of autoimmunity, and has also been reported in patients treated with PD-1 blockade, suggesting that PD-1 might regulate this process. Autoantibody production results from B cell:CD4+ T cell interactions in the germinal center of the lymph node. The dynamics and regulation of the germinal center in spontaneous autoimmunity and after PD-1 blockade are not well understood, primarily due to an inability to track self-specific lymphocytes. To bridge this knowledge gap, we used tetramers to phenotype islet-specific CD4+ T cells and B cells in mice. PD-1- or PD-L1-deficient mice, as well as NOD mice treated with anti-PD-1, had increased insulin autoantibodies, as well as increased insulin-specific T follicular helper CD4+ T cells and germinal center B cells compared to controls. This increase was dependent on CD4+ T cell-intrinsic PD-1 signaling and relied on peptide:MHCII recognition. Taken together, my thesis work provides a mechanistic explanation for autoantibody onset following PD-1 blockade in the clinic, and has important implications for cancer immunotherapy and autoimmunity.
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    Regulation of the kinases LynA and LynB and function in autoimmune disease
    (2021-04) Brian, Ben
    Cell-surface receptors on immune cells direct immune-cell function by sensing and responding to signs of pathogens and tissue damage. Signaling initiated by immunoreceptors is responsible for essential aspects of the immune response, including phagocytosis by myeloid cells, and antigen sensing by B and T cells. Efficient regulation of immunoreceptor signaling ensures that inflammation arising from pathogen clearance is limited in order to prevent tissue damage. Autoimmune diseases, such as systemic lupus erythematosus, can occur when these signaling pathways are improperly regulated. The tyrosine kinase Lyn is an important regulator of immune function due to its unique ability to both initiate signaling that can generate inflammation, and also recruit and activate proteins that dampen cellular activation. Alterations to Lyn expression and signaling in both human and mice can worsen or cause autoimmune disease. Understanding how Lyn is regulated and balances these roles is necessary to develop therapies that selectively limit autoinflammation but preserve pathogen clearance. Alternative splicing of the lyn gene produces two proteins, LynA and LynB, that differ by the presence of a 21-amino-acid insert present in LynA and absent in LynB. Here, we demonstrate the LynA and LynB are differentially regulated in immune cells. Phosphorylation of LynA at Tyrosine 32 in its unique region causes LynA to be rapidly, and selectively, poly-ubiquitinated by an E3 ligase, c-Cbl, and degraded. We show that differential expression of c-Cbl in macrophages and mast cells controls LynA protein levels, degradation, and signaling responses following Src-family kinase activation. Furthermore, we created novel knockout mice to study the roles LynA and LynB play in regulating autoimmune disease. Using these novel mice, we show that LynB prevents the development of splenomegaly and autoimmunity by limiting myeloid cell expansion and B cell activation. We also demonstrate that LynB-deficient mice have elevated responses to Toll-like receptor activation. Together, these results indicate that LynA and LynB are differentially regulated and have unique roles in the immune response. Therefore, understanding LynA and LynB signaling and regulation could yield targets that limit inflammation but preserve normal immune function.