IU Indianapolis ScholarWorks :: Browsing by Subject "Germinal center"

Browsing by Subject "Germinal center"

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Dynamic modulation of spleen germinal center reactions by gut bacteria during Plasmodium infection
(Cell Press, 2021-05-11) Mandal, Rabindra K.; Denny, Joshua E.; Namazzi, Ruth; Opoka, Robert O.; Datta, Dibyadyuti; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of Medicine
Gut microbiota educate the local and distal immune system in early life to imprint long-term immunological outcomes while maintaining the capacity to dynamically modulate the local mucosal immune system throughout life. It is unknown whether gut microbiota provide signals that dynamically regulate distal immune responses following an extra-gastrointestinal infection. We show here that gut bacteria composition correlated with the severity of malaria in children. Using the murine model of malaria, we demonstrate that parasite burden and spleen germinal center reactions are malleable to dynamic cues provided by gut bacteria. Whereas antibiotic-induced changes in gut bacteria have been associated with immunopathology or impairment of immunity, the data demonstrate that antibiotic-induced changes in gut bacteria can enhance immunity to Plasmodium. This effect is not universal but depends on baseline gut bacteria composition. These data demonstrate the dynamic communications that exist among gut bacteria, the gut-distal immune system, and control of Plasmodium infection.
Evidence that High Affinity IgE Can Develop in the Germinal Center in the Absence of an IgG1-switched Intermediate
(American Association of Immunologists, 2023) Chen, Qiang; Liu, Hong; Luling, Noelle; Reinke, Julia; Dent, Alexander L.; Microbiology and Immunology, School of Medicine
High affinity allergen-specific IgE is essential for the severe allergic anaphylaxis response. High affinity antibodies (Abs) are formed by successive rounds of selection of Ag-specific B cells in the germinal center (GC), however several studies have shown that IgE+ GC B cells are impaired in their ability to undergo selection in the GC. A pathway, known as the “indirect switching pathway” for IgE, has been described whereby Ag-specific B cells initially switch to the IgG1 isotype and undergo affinity selection in the GC, with a secondary switch to the IgE isotype after affinity selection. In previous work, using a food allergy model in mice, we investigated how high affinity IgE develops in the GC but we did not test the indirect switching model. Here we analyzed the importance of the indirect switching pathway by constructing IgG1-cre Bcl6-fl/fl mice. In these mice, once B cells switch to IgG1, they delete Bcl6 and thus cannot enter or persist in the GC. When we tested IgG1-cre Bcl6-fl/fl mice with our food allergy model, we found that as expected, IgG1 Abs had decreased affinity, but unexpectedly the affinity of IgE for allergen was unchanged. IgG1-cre Bcl6-fl/fl mice underwent anaphylaxis in response to allergen, consistent with the formation of high affinity IgE. Thus, in a food allergy response, high affinity IgE can be efficiently formed in the absence of indirect switching to IgG1, either by direct selection of IgE+ GC B cells or indirect selection of IgM+ GC B cells that later switch to IgE.
Gut Microbiota Composition Modulates the Magnitude and Quality of Germinal Centers during Plasmodium Infections
(Cell Press, 2020-12-15) Waide, Morgan L.; Polidoro, Rafael; Powell, Whitney L.; Denny, Joshua E.; Kos, Justin; Tieri, David A.; Watson, Corey T.; Schmidt, Nathan W.; Pediatrics, School of Medicine
Gut microbiota composition is associated with human and rodent Plasmodium infections, yet the mechanism by which gut microbiota affects the severity of malaria remains unknown. Humoral immunity is critical in mediating the clearance of Plasmodium blood stage infections, prompting the hypothesis that mice with gut microbiota-dependent decreases in parasite burden exhibit better germinal center (GC) responses. In support of this hypothesis, mice with a low parasite burden exhibit increases in GC B cell numbers and parasite-specific antibody titers, as well as better maintenance of GC structures and a more targeted, qualitatively different antibody response. This enhanced humoral immunity affects memory, as mice with a low parasite burden exhibit robust protection against challenge with a heterologous, lethal Plasmodium species. These results demonstrate that gut microbiota composition influences the biology of spleen GCs as well as the titer and repertoire of parasite-specific antibodies, identifying potential approaches to develop optimal treatments for malaria.
IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells
(American Association for the Advancement of Science, 2023) Luo, Wei; Conter, Laura; Elsner, Rebecca A.; Smita, Shuchi; Weisel, Florian; Callahan, Derrick; Wu, Shuxian; Chikina, Maria; Shlomchik, Mark; Microbiology and Immunology, School of Medicine
Both B cell receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to synergistically induce c-MYC and phosphorylated S6 ribosomal protein (p-S6), markers of positive selection. How interleukin-21 (IL-21), a key T follicular helper (TFH)-derived cytokine, affects GCBCs is unclear. Like BCR and CD40 signals, IL-21 receptor (IL-21R) plus CD40 signals also synergize to induce c-MYC and p-S6 in GCBCs. However, IL-21R plus CD40 stimulation differentially affects GCBC fate compared with BCR plus CD40 ligation-engaging unique molecular mechanisms-as revealed by bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry of GCBCs in vitro and in vivo. Whereas both signal pairs induced BLIMP1 in some GCBCs, only the IL-21R/CD40 combination induced IRF4hi/CD138+ cells, indicative of plasma cell differentiation, along with CCR6+/CD38+ memory B cell precursors. These findings reveal a second positive selection pathway in GCBCs, document rewired IL-21R signaling in GCBCs, and link specific TFH- and Ag-derived signals to GCBC differentiation.
Ipsilateral immunization after a prior SARS-CoV-2 mRNA vaccination elicits superior B cell responses compared to contralateral immunization
(Elsevier, 2024) Jiang, Wenxia; Maldeney, Alexander R.; Yuan, Xue; Richer, Martin J.; Renshaw, Scott E.; Luo, Wei; Microbiology and Immunology, School of Medicine
mRNA vaccines have proven to be pivotal in the fight against COVID-19. A recommended booster, given 3 to 4 weeks post the initial vaccination, can substantially amplify protective antibody levels. Here, we show that, compared to contralateral boost, ipsilateral boost of the SARS-CoV-2 mRNA vaccine induces more germinal center B cells (GCBCs) specific to the receptor binding domain (RBD) and generates more bone marrow plasma cells. Ipsilateral boost can more rapidly generate high-affinity RBD-specific antibodies with improved cross-reactivity to the Omicron variant. Mechanistically, the ipsilateral boost promotes the positive selection and plasma cell differentiation of pre-existing GCBCs from the prior vaccination, associated with the expansion of T follicular helper cells. Furthermore, we show that ipsilateral immunization with an unrelated antigen after a prior mRNA vaccination enhances the germinal center and antibody responses to the new antigen compared to contralateral immunization. These findings propose feasible approaches to optimize vaccine effectiveness.
Regulation of the germinal center reaction by T helper cells and T regulatory cells
(2016-04-11) Wu, Hao; Dent, Alexander L.; Kaplan, Mark H.; Turner, Matthew J.; Zhou, Baohua
Germinal Centers (GCs) are transient lymphoid structures that arise in lymphoid organs in response to T cell-dependent antigen. Within the GC, follicular T helper (TFH) cells promote GC B cell differentiation and in turn the proper antibody production to protect us from invading pathogens. We wished to study the regulation of this process by transcription factors STAT3 and Bcl6. STAT3 is important for both TFH cell differentiation and IL-4 production by Th2 cells. IL-4 is a major functional cytokine produced by TFH cells. To dissect the role of STAT3 in IL-4 production by TFH cells, we generated T cell-specific conditional STAT3 knockout mice (STAT3KO). Compared to WT mice, TFH cell differentiation in STAT3KO mice was partially impaired, both in spleen following sheep red blood cells (SRBC) immunization and in Peyer's patches (PPs). In STAT3KO mice, the numbers of splenic GC B cells were markedly decreased, whereas PP GC B cells developed at normal numbers and IgG1 class switching was greatly increased. Unexpectedly, we found that STAT3 intrinsically suppressed the expression of IL-4 and Bcl6 in TFH cells. Mechanistically, in vitro repression of IL-4 expression in CD4 T cells by Bcl6 required STAT3 function. Apart from TFH cells, the GC reaction is also controlled by regulatory follicular T helper (TFR) cells, a subset of Treg cells. To study the mechanism of how TFR cells regulate the GC reaction, we generated mice specifically lacking TFR cells by specifically deleting Bcl6 in Treg cells. Following immunization, these "Bcl6FC" mice developed normal TFH and GC B cell populations. However, Bcl6FC mice produced altered antigen-specific antibody responses, with reduced titers of IgG and increased IgA. Bcl6FC mice also developed IgG antibodies with significantly decreased avidity to antigen in an HIV-1 gp120 "prime-boost" vaccine model. Additionally, TFH cells from Bcl6FC mice produced higher levels of Interferon-γ, IL-10 and IL-21. Loss of TFR cells therefore leads to highly abnormal TFH and GC B cell responses. Overall, our studies have uncovered unexpected regulatory roles of STAT3 in TFH cell function as well as the novel regulatory roles of TFR cells on cytokine production by TFH cells and on antibody production.
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.
Stat3 Is Important for Follicular Regulatory T Cell Differentiation
(Plos, 2016-05-05) Wu, Hao; Xie, Markus M.; Liu, Hong; Dent, Alexander; Department of Microbiology & Immunology, IU School of Medicine
The production of antibody is precisely controlled during the germinal center (GC) reaction. This process is dependent on the help from follicular T helper (Tfh) cells to germinal center (GC) B cells and is regulated by regulatory follicular T helper (Tfr) cells. How Tfr cells develop and how their suppressive activity functions are not well understood. Here, we found that Stat3 is indispensible for Tfr cell differentiation. After immunization with Sheep Red Blood Cells (SRBC), the loss of Tfr cells caused by deletion of Stat3 in Treg cells does not affect the size of Tfh or GC B cell population, but rather leads to strongly enhanced production of antigen-specific IgG1 and IgG2b. In Peyer's patches (PPs) in the gut, we found that Stat3 expression in Treg cells is also required for Tfr cell formation to commensal organisms. However, loss of Tfr cells in the gut did not affect the numbers of Tfh cells and GC B cells, nor affect IgG1 or IgA switching by GC B cells. Overall, our study has uncovered unique roles of Stat3 in Tfr cell differentiation and the regulation of the antibody response.
STAT4 Is Largely Dispensable for Systemic Lupus Erythematosus-like Autoimmune- and Foreign Antigen-Driven Antibody-Forming Cell, Germinal Center, and Follicular Th Cell Responses
(American Association of Immunologists, 2021-01-14) Fike, Adam J.; Chodisetti, Sathi Babu; Bricker, Kristen N.; Choi, Nicholas M.; Chroneos, Zissis C.; Kaplan, Mark H.; Rahman, Ziaur S. M.; Microbiology and Immunology, School of Medicine
Genome-wide association studies identified variants in the transcription factor STAT4 gene and several other genes in the STAT4 signaling pathway, such as IL12A, IL12B, JAK2, and TYK2, which are associated with an increased risk of developing systemic lupus erythematosus (SLE) and other autoimmune diseases. Consistent with the genome-wide association studies data, STAT4 was shown to play an important role in autoimmune responses and autoimmunity development in SLE mouse models. Despite such important role for STAT4 in SLE development in mice and humans, little is known whether and how STAT4 may regulate extrafollicular Ab-forming cell (AFC) and follicular germinal center (GC) responses, two major pathways of autoreactive B cell development and autoantibody production. To our surprise, we found STAT4 to be largely dispensable for promoting autoimmune AFC and GC responses in various autoimmune- and SLE-prone mouse models, which strongly correlated with autoantibody production, and immune complex deposition and immune cell infiltration in the kidney. We further observed that STAT4 deficiency had no effects on AFC, GC, and Ag-specific Ab responses during protein Ag immunization or influenza virus infection. Additionally, CD4+ effector and follicular Th cell responses in autoimmune- and SLE-prone mice and protein Ag-immunized and influenza virus-infected mice were intact in the absence of STAT4. Together, our data demonstrate a largely dispensable role for STAT4 in AFC, GC, and Ab responses in SLE mouse models and in certain foreign Ag-driven responses.
T Follicular Regulatory Cells Promote the Germinal Center Reaction and Allergic IgE Response While Repressing Abnormal Differentiation of T Follicular Helper Cells
(2019-05) Xie, Ming; Dent, Alexander L.; Dong, X. Charlie; Kaplan, Mark H.; Zhou, Baohua
Follicular T helper (TFH) and regulatory (TFR) cells are two key classes of CD4+ T cells found in germinal centers (GCs). The primary role of TFH cells is to help B cells form GCs to produce high-affinity antibodies during an infection while the role of TFR cells remains controversial. The transcriptional repressor Bcl6 is essential for the differentiation of TFH, TFR and GCB cells and understanding signaling pathways that induce Bcl6 and TFH cell differentiation are important. We observed that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation by a pathway involving the metabolic sensor AMP kinase. The transcription factor Blimp1 represses both TFH cell differentiation and Bcl6 expression, and we show the major role of Blimp1 on TFH cell differentiation is to repress Bcl6 expression and not other genes in the TFH differentiation pathway. We also found Bcl6 positively regulates expression of the key TFH cell receptor PD-1 by inhibiting the repression of PD-1 by the transcription factor Tbet. The roles of TFH and TFR cells in controlling allergen-specific IgE were investigated using a peanut allergy model and strains of mice with alterations in the TFH and TFR pathways. We found TFR cells unexpectedly play an essential role in promoting and maintaining IgE production and anaphylaxis, as well as the GC reaction. Compared to control mice, TFR-deficient mice lacked circulating peanut-specific IgE and anaphylactic responses were significantly weakened. Mechanistically, TFR cells require Blimp1 controlled IL-10 to promote GCB cell survival and IgE production. Blocking IL-10 signals mimicked the loss of IgE levels in TFR-deficient mice and rescued mice from anaphylaxis. Overall, these studies have defined novel roles of Bcl6, TFH and TFR cells in regulating antibody production by the GC reaction, and provide greater understanding of how allergic immune responses are controlled.

Browsing by Subject "Germinal center"

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