Browsing by Author "Read, Kaitlin A."

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    Control of lupus nephritis by changes of gut microbiota
    Mu, Qinghui; Zhang, Husen; Liao, Xiaofeng; Lin, Kaisen; Liu, Hualan; Edwards, Michael R.; Ahmed, Sattar Ansar; Yuan, Ruoxi; Li, Liwu; Cecere, Thomas E.; Branson, David B.; Kirby, Jay L.; Goswami, Poorna; Leeth, Caroline M.; Read, Kaitlin A.; Oestreich, Kenneth J.; Vieson, Miranda D.; Reilly, Christopher M.; Luo, Xin M. (2017-07-11)
    Background: Systemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure. Immunosuppressants used in treatment put patients at a higher risk of infections. New knowledge of disease modulators, such as symbiotic bacteria, can enable fine-tuning of parts of the immune system, rather than suppressing it altogether. Results: Dysbiosis of gut microbiota promotes autoimmune disorders that damage extraintestinal organs. Here we report a role of gut microbiota in the pathogenesis of renal dysfunction in lupus. Using a classical model of lupus nephritis, MRL/lpr, we found a marked depletion of Lactobacillales in the gut microbiota. Increasing Lactobacillales in the gut improved renal function of these mice and prolonged their survival. We used a mixture of 5 Lactobacillus strains (Lactobacillus oris, Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus johnsonii, and Lactobacillus gasseri), but L. reuteri and an uncultured Lactobacillus sp. accounted for most of the observed effects. Further studies revealed that MRL/lpr mice possessed a “leaky” gut, which was reversed by increased Lactobacillus colonization. Lactobacillus treatment contributed to an anti-inflammatory environment by decreasing IL-6 and increasing IL-10 production in the gut. In the circulation, Lactobacillus treatment increased IL-10 and decreased IgG2a that is considered to be a major immune deposit in the kidney of MRL/lpr mice. Inside the kidney, Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. These beneficial effects were present in female and castrated male mice, but not in intact males, suggesting that the gut microbiota controls lupus nephritis in a sex hormone-dependent manner. Conclusions: This work demonstrates essential mechanisms on how changes of the gut microbiota regulate lupusassociated immune responses in mice. Future studies are warranted to determine if these results can be replicated in human subjects.
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    IL-12 signaling drives the differentiation and function of a T(H)1-derived T-FH1-like cell population
    Powell, Michael D.; Read, Kaitlin A.; Sreekumar, Bharath K.; Jones, Devin M.; Oestreich, Kenneth J. (Springer Nature, 2019-09-30)
    CD4(+) T follicular helper (T-FH) cells provide help to B cells and promote antibody-mediated immune responses. Increasing evidence supports the existence of T-FH populations that secrete cytokines typically associated with the effector functions of other CD4(+) T cell subsets. These include T helper 1 (T(H)1)-biased T-FH (T-FH(1)) cells that have recognized roles in both immune responses to pathogens and also the pathogenesis of autoimmune disease. Given their apparent importance to human health, there is interest in understanding the mechanisms that regulate T-FH1 cell formation and function. However, their origin and the molecular requirements for their differentiation are unclear. Here, we describe a population of murineT(H)1-derived,T-FH1-like cells that express the chemokine receptor Cxcr3 and produce both the T(H)1 cytokine interferon-gamma and the T-FH-associated cytokine interleu kin-21 (IL-21). Furthermore, these T-FH1-like cells promote B cell activation and antibody production at levels indistinguishable from conventional IL-6-derived T-FH-like cells. Regarding their regulatory requirements, we find that IL-12 signaling is necessary for the differentiation and function of this T-FH1-like cell population. Specifically, IL-12-dependent activation of STAT4, and unexpectedly STAT3, promotes increased expression of IL-21 and the T-FH lineage-defining transcription factor Bcl-6 in T-FH1-like cells. Taken together, these findings provide insight into the potential origin and differentiation requirements of T-FH1 cells.
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    IL-7 signalling represses Bcl-6 and the TFH gene Program
    McDonald, Paul W.; Read, Kaitlin A.; Baker, Chandra E.; Anderson, Ashlyn E.; Powell, Michael D.; Ballesteros-Tato, André; Oestreich, Kenneth J. (Nature, 2016-01-08)
    The transcriptional repressor Bcl-6 is linked to the development of both CD4⁺ T follicular helper (TFH) and central memory T (TCM) cells. Here, we demonstrate that in response to decreased IL-2 signalling, T helper 1 (TH1) cells upregulate Bcl-6 and co-initiate TFH- and TCM-like gene programs, including expression of the cytokine receptors IL-6R∝ and IL-7R. Exposure of this potentially bi-potent cell population to IL-6 favours the TFH gene program, whereas IL-7 signalling represses TFH-associated genes including Bcl6 and Cxcr5, but not the TCM-related genes Klf2 and Sell. Mechanistically, IL-7-dependent activation of STAT5 contributes to Bcl-6 repression. Importantly, antigen-specific IL-6R∝⁺IL-7R⁺ CD4⁺ T cells emerge from the effector population at late time points post influenza infection. These data support a novel role for IL-7 in the repression of the TFH gene program and evoke a divergent regulatory mechanism by which post-effector TH1 cells may contribute to long-term cell-mediated and humoral immunity.
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    Selective Histone Deacetylase 6 Inhibition Normalizes B Cell Activation and Germinal Center Formation in a Model of Systemic Lupus Erythematosus
    Ren, Jingjing; Catalina, Michelle D.; Eden, Kristin; Liao, Xiaofeng; Read, Kaitlin A.; Luo, Xin M.; McMillan, Ryan P.; Hulver, Matthew W.; Jarpe, Matthew; Bachali, Prathyusha; Grammer, Amrie C.; Lipsky, Peter E.; Reilly, Christopher M. (2019-10-25)
    Autoantibody production by plasma cells (PCs) plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The molecular pathways by which B cells become pathogenic PC secreting autoantibodies in SLE are incompletely characterized. Histone deactylase 6 (HDAC6) is a unique cytoplasmic HDAC that modifies the interaction of a number of tubulin- associated proteins; inhibition of HDAC6 has been shown to be beneficial in murine models of SLE, but the downstream pathways accounting for the therapeutic benefit have not been clearly delineated. In the current study, we sought to determine whether selective HDAC6 inhibition would abrogate abnormal B cell activation in SLE. We treated NZB/W lupus mice with the selective HDAC6 inhibitor, ACY-738, for 4 weeks beginning at 20 weeks-of age. After only 4 weeks of treatment, manifestation of lupus nephritis (LN) were greatly reduced in these animals. We then used RNAseq to determine the genomic signatures of splenocytes from treated and untreated mice and applied computational cellular and pathway analysis to reveal multiple signaling events associated with B cell activation and differentiation in SLE that were modulated by HDAC6 inhibition. PC development was abrogated and germinal center (GC) formation was greatly reduced. When the HDAC6 inhibitor-treated lupus mouse gene signatures were compared to human lupus patient gene signatures, the results showed numerous immune, and inflammatory pathways increased in active human lupus were significantly decreased in the HDAC6 inhibitor treated animals. Pathway analysis suggested alterations in cellular metabolism might contribute to the normalization of lupus mouse spleen genomic signatures, and this was confirmed by direct measurement of the impact of the HDAC6 inhibitor on metabolic activities of murine spleen cells. Taken together, these studies show HDAC6 inhibition decreases B cell activation signaling pathways and reduces PC differentiation in SLE and suggest that a critical event might be modulation of cellular metabolism.
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    Trans-presentation of IL-15 modulates STAT5 activation and Bcl-6 expression in TH1 cells
    Cooley, Ian D.; Read, Kaitlin A.; Oestreich, Kenneth J. (Nature, 2015-10-26)
    During infection, naïve CD₄⁺ T helper cells differentiate into specialized effector subsets based upon environmental signals propagated by the cytokine milieu. Recently, this paradigm has been complicated by the demonstration that alterations in the cytokine environment can result in varying degrees of plasticity between effector T helper cell populations. Therefore, elucidation of the mechanisms by which cytokines regulate T helper cell differentiation decisions is increasingly important. The gamma common cytokine IL-15 is currently undergoing clinical trials for the treatment of malignancies, due to its well-established role in the regulation of natural killer and CD8⁺T cell immune responses. However, the effect of IL-15 signaling on CD4₄⁺ T cell activity is incompletely understood. One mechanism by which IL-15 activity is conferred is through transpresentation via the IL-15 receptor alpha subunit. Here, we demonstrate that differentiated TH1 cells are responsive to trans-presented IL-15. Importantly, while trans-presentation of IL-15 results in STAT5 activation and maintenance of the TH1 gene program, IL-15 treatment alone allows for increased Bcl-6 expression and the upregulation of a TFH-like profile. Collectively, these findings describe a novel role for IL-15 in the modulation of CD₄⁺T cell responses and provide valuable insight for the use of IL-15 in immunotherapeutic approaches.