Browsing by Subject "BCL6"

Now showing 1 - 3 of 3
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    BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection
    (National Academy of Sciences, 2019-06-11) Zhu, Bibo; Zhang, Ruixuan; Li, Chaofan; Jiang, Li; Xiang, Min; Ye, Zhenqing; Kita, Hirohito; Melnick, Ari M.; Dent, Alexander L.; Sun, Jie; Pediatrics, School of Medicine
    Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.
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    Elucidating the role of BCL6 in helper T cell activation, proliferation, and differentiation
    (2014) Hollister, Kristin N.; Dent, Alexander L.; Brutkiewicz, Randy R.; Harrington, Maureen A.; Kaplan, Mark H.
    The transcriptional repressor BCL6 has been shown to be essential for the differentiation of germinal center (GC) B cells and follicular T helper (TFH) cells. The interaction of TFH and GC B cells is necessary for the development of high affinity antibodies specific for an invading pathogen. Germline BCL6-deficient mouse models limit our ability to study BCL6 function in T cells due to the strong inflammatory responses seen in these mice. To overcome this, our lab has developed a new BCL6 conditional knockout (cKO) mouse using the cre/lox system, wherein the zinc finger region of the BCL6 gene is flanked by loxP sites. Mating to a CD4-Cre mouse allowed us to study the effects of BCL6 loss specifically in T cells, without the confounding effects seen in germline knockout models. Using this cKO model, we have reaffirmed the necessity of BCL6 for TFH differentiation, including its role in sustained CXCR5 surface expression, a signature marker for TFH cells. This model also allowed us to recognize the role of BCL6 in promoting the expression of PD-1, another key surface marker for TFH cells. Without BCL6, CD4+ T cells cannot express PD-1 at the high levels seen on TFH cells. Our discovery of DNMT3b as a target for BCL6 suggests BCL6-deficient T cells have increased DNA methyltransferase activity at the PD-1 promoter. This data establishes a novel pathway for explaining how BCL6, a transcriptional repressor, can activate genes. Experiments with the BCL6 cKO model have also established a role for BCL6 in naïve CD4+ T cell activation. Furthermore, we did not observe increased differentiation of other helper T cell subsets, in contrast to what has been reported elsewhere with germline BCL6-deficient models. Unexpectedly, we found decreased T helper type 2 (Th2) cells, whereas mouse models with a germline mutation of BCL6 have increased Th2 cells. These results indicate that BCL6 activity in non-T cells is critical for controlling T cell differentiation. Finally, using an HIV-1 gp120 immunization model, we have, for the first time, shown BCL6-dependent GCs to be limiting for antibody development and affinity maturation in a prime-boost vaccine scheme.
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    The role of follicular helper T cells and the germinal center in HIV-1 gp120 DNA prime and gp120 protein boost vaccination
    (Taylor & Francis, 2014-07) Hollister, Kristin; Chen, Yuxin; Wang, Shixia; Wu, Hao; Mondal, Arpita; Clegg, Ninah; Lu, Shan; Dent, Alexander; Department of Microbiology and Immunology, IU School of Medicine
    The importance of follicular T helper (TFH) cells and the germinal center (GC) reaction in the humoral immune response has become clear in recent years, however the role of TFH cells and the GC in an HIV vaccine strategy remains unclear. In this study, we primed mice with gp120-encoding DNA and boosted with gp120 protein, a regimen previously shown to induce high titers of high affinity and cross-reactive anti-gp120 Abs. Priming with gp120 DNA caused increased TFH cell differentiation, GC B cells, and antigen-specific antibody titers, compared with priming with gp120 protein. Priming with DNA also caused more activated CD4(+) T cells to become TFH cells and more GC B cells to become memory cells. Deletion of BCL6 midway through the vaccine regimen resulted in loss of TFH cells and GCs, and, unexpectedly, increased anti-gp120 IgG titers and avidity. Our data suggests vaccination with gp120-encoding DNA elicits a stronger and more rapid TFH and GC response than gp120 protein. Furthermore, we demonstrate that the GC reaction may actually limit antigen-specific IgG secretion in the context of repeated immunizations.