On the carrying capacity of the bone marrow survival niche in mice.
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2025-01
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Plasmacytes, the effector arm of humoral immunity, produce sufficient amounts of specific antibodies to provide protection against infection or disease. The durability of this humoral protection depends on the generation of long-lived plasmacytes (LLPC), a specialized population that is capable of secreting antibody over long periods of times - years to decades. Here we investigate the role of constitutively active germinal centers (GCs) in generating the plasmacytes resident in bone marrow, a site critical for vaccine-induced LLPC to provide meaningful protection to infection and resistance to morbidity. In unimmunized B6.S1pr2-Cre mice, we show that a short period of conditional labeling marks 85% of gut-associated GC B cells and their progeny. Frequencies of labeled GC B cells fall over time, but frequencies of labeled bone marrow PC increase to approximately one-third of all bone marrow PC by 70-80 days after pulse labeling. Labeled, GC derived bone marrow PC express the identical isotypic distribution of the unlabeled PC in bone marrow. We conclude that the progeny of gut-associated GC B cells are responsible for most, and perhaps all, bone marrow PC and that under homeostatic conditions, serum antibody reflects exposure to gut antigens. Bone marrow occupancy by these gut-derived PC raises the possibility of competition with more transient, vaccine-induced humoral responses.
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Tonouchi, Keisuke, Chen-Hao Yeh, Derek W Cain, E Ashley Moseman, Barton F Haynes, Kshitij Wagh, Kevin Wiehe, Tomohiro Kurosaki, et al. (2025). On the carrying capacity of the bone marrow survival niche in mice. Frontiers in immunology, 16. p. 1706810. 10.3389/fimmu.2025.1706810 Retrieved from https://hdl.handle.net/10161/33841.
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Scholars@Duke
Chen-Hao Yeh
Dr. Yeh completed his undergraduate and Master of Science degree at the National Taiwan University in Taipei. He then pursued his Ph.D. at the University of Tokyo in Japan. He moved to Durham in 2015 for postdoctoral training in Dr. Garnett Kelsoe’s laboratory at the Duke Department of Immunology.
Dr. Yeh holds a broad academic background in biochemistry and immunology, with specific training and expertise in lymphocyte development and differentiation. His research has focused on: 1) germinal center (GC) B cell selection, differentiation and antibody affinity maturation and 2) T follicular helper (Tfh) cell differentiation and TCR repertoire analysis.
Over the years, Dr. Yeh has demonstrated that B-cell selection based on surface pMHCII density is stringent in the establishment of GCs, but relatively relaxed during GC responses; this observation has led to fundamental revisions in the standard models for affinity-driven selection. With multiple genetic models to identify GC-resident Tfh cells in the mouse, Dr. Yeh also showed that the standard phenotypic definition of “GCTfh” included a majority of T cells that do not enter GCs. The more abundant Tfh-like cells have distinct developmental requirements, TCR repertoires and transcriptomic profiles compared to the rarer GC-resident Tfh cells, implying distinct physiologies and function. In addition, Dr. Yeh has categorized the phenotype of memory and GC B cell populations in Rhesus macaque (RM) as a step forward in understanding humoral responses in RMs and to enable isolation of live GC B cells for in vitro culture.
Derek Wilson Cain
My research focuses on the interactions of T cells and B cells during infection or following vaccination. I am particularly interested in the inter- and intracellular events that take place within germinal centers, the anatomic site of antibody evolution during an immune response.
Ashley Moseman
Our lab seeks to understand central nervous system (CNS) immunity, with a specific focus on antimicrobial protection at the olfactory barrier. Barrier immunity, particularly at mucosal surfaces, has received a great deal of interest within the immunological community. Unlike classical barrier surfaces in the gut, lower respiratory tract, and skin, the olfactory neuroepithelial barrier is unique in its dedication to neuronal function. Olfactory sensory neurons (OSNs) must contact the external environment to perform their chemosensory functions, but this provides a direct link between the outside world and the CNS. For these reasons, our lab seeks to define the mechanisms by which immunological surveillance and the immune response within the olfactory epithelium is tailored to support both barrier and neurosensory functions while warding off neurotropic pathogens.
We are also strong believers that visualizing cellular behavior in vivo can guide mechanistic discovery. To this end, we employ multiphoton intravital imaging to analyze in vivo CNS immune responses and determine how these responses are tailored to the CNS environment. Within the CNS, intravital imaging has allowed us to observe dynamic in vivo antigen engagement by T cell subsets during viral infection as well as innate immune responses to Naegleria fowleri infection.
Lab Website
Barton Ford Haynes
Barton F. Haynes, M.D. is the Frederic M. Hanes Professor of Medicine and Immunology, and Director of the Duke Human Vaccine Institute. Prior to leading the DHVI, Dr. Haynes served as Chief of the Division of Rheumatology, Allergy and Clinical Immunology, and later as Chair of the Department of Medicine. As Director of the Duke Human Vaccine Institute, Bart Haynes is leading a team of investigators working on vaccines for emerging infections, including tuberculosis, pandemic influenza, emerging coronaviruses, and HIV/AIDS.
To work on the AIDS vaccine problem, his group has been awarded two large consortium grants from the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) known as the Center for HIV/AIDS Vaccine Immunology (CHAVI) (2005-2012), and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) (2012-2019) to conduct discovery science to speed HIV vaccine development. In July 2019, his team received the third of NIH “CHAVI” awards to complete the HIV vaccine development work - CHAV-D.
Since the beginning of the COVID-19 pandemic, Haynes and the DHVI Team has been working non-stop to develop vaccines, rapid and inexpensive tests and therapeutics to combat the pandemic. Since March 2020, he has served as a member of the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) committee to advise on COVID-19 vaccine development, and served as the co-chair of the ACTIV subcommittee on vaccine safety. Haynes is the winner of the Alexander Fleming Award from the Infectious Disease Society of America and the Ralph Steinman Award for Human Immunology Research from the American Association of Immunologists. He is a member of the National Academy of Medicine, National Academy of Inventors and the American Academy of Arts and Sciences.
About the Haynes LaboratoryThe Haynes lab is studying host innate and adaptive immune responses to the human immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the enabling technology to make preventive vaccines against these three major infectious diseases.
Mucosal Immune Responses in Acute HIV Infection
The Haynes lab is working to determine why broadly neutralizing antibodies are rarely made in acute HIV infection (AHI), currently a major obstacle in the development of an HIV vaccine. The lab has developed a novel approach to define the B cell repertories in AHI in order to find neutralizing antibodies against the virus. This approach uses linear Immunoglobulin (Ig) heavy and light chain gene expression cassettes to express Ig V(H) and V(L) genes isolated from sorted single B cells as IgG1 antibody without a cloning step. This strategy was used to characterize the Ig repertoire of plasma cells/plasmablasts in AHI and to produce recombinant influenza mAbs from sorted single human plasmablasts after influenza vaccination.
The lab is also studying the earliest effect HIV-1 has on B cells. Analyzing blood and gut-associated lymphoid tissues (GALT) during acute HIV infection, they have found that as early as 17 days after transmission HIV-1 induces B cell class switching and 47 days after transmission, HIV-1 causes considerable damage to GALT germinal centers. They found that in AHI, GALT memory B cells induce polyclonal B cell activation due to the presence of HIV-1-specific, influenza-specific, and autoreactive antibodies. The team concluded from this study that early induction of polyclonal B cell differentiation, along with follicular damage and germinal center loss, may explain why HIV-1 induced antibody responses decline rapidly during acute HIV infection and why plasma antibody responses are delayed.
The lab is also looking at ways of generating long-lived memory B cell responses to HIV infection, another major hurdle in the development of a successful HIV-1 vaccine. The lab has found that in HIV-1 gp120 envelope vaccination and chronic HIV-1 infection, HIV-1 envelope induces predominantly short-lived memory B cell-dependent plasma antibodies.
Immunogen Design
To overcome the high level of genetic diversity in HIV-1 envelope genes, the Haynes lab is developing strategies to induce antibodies that cross-react with multiple strains of HIV. The lab has designed immunogens based on transmitted founder Envs and mosaic consensus Envs in collaboration with Dr. Bette Korber at Los Alamos National Laboratory. These immunogens are designed to induce antibodies that cross-react with a multiple subtype Env glycoproteins. The goal is to determine if cross-reactive mAbs to highly conserved epitopes in HIV-1 envelope glycoproteins can be induced. The team recently characterized a panel of ten mAbs that reacted with varying breadth to subtypes A, B, C, D, F, G, CRF01_AE, and a highly divergent SIVcpzUS Env protein. Two of the mAbs cross-reacted with all tested Env proteins, including SIVcpzUS Env and bound Env proteins with high affinity.
Mucosal Immune Responses in TB and Influenza
The Haynes lab is helping to develop novel approaches to TB vaccine development. The current therapeutic vaccine for TB, called BCG, may prevent complications from TB in children, but offers little protection against infection and disease in adults. The lab is focused on using live attenuated Mycobacterium tuberculosis mutants as vaccine candidates and is currently evaluating this approach in non-human primate studies. As part of the DHVI Influenza program, they are studying the B cell response to influenza in order to generate a “universal” flu vaccine. They are currently trying to express more highly conserved influenza antigens in recombinant vesicular stomatitis virus (rVSV) vectors in order to elicit robust T cell and antibody responses to those antigens.
Kshitij G. Wagh
Kevin J Wiehe
Dr. Kevin Wiehe is the director of research, director of computational biology and co-director of the Quantitative Research Division at the Duke Human Vaccine Institute (DHVI). He has over 20 years of experience in the field of computational biology and has expertise in computational structural biology, computational genomics, and computational immunology.
For the past decade, he has applied his unique background to developing computational approaches for studying the B cell response in both the infection and vaccination settings. He has utilized his expertise in computational structural biology to structurally model and characterize HIV and influenza antibody recognition. Dr. Wiehe has utilized his expertise in computational genomics and computational immunology to develop software to analyze large scale next generation sequencing data of antibody repertoires as well as develop computational programs for estimating antibody mutation probabilities. Dr. Wiehe has shown that low probability antibody mutations can act as rate-limiting steps in the development of broadly neutralizing antibodies in HIV.
Through his PhD, postdoc work, and now his roles at DHVI, Dr. Wiehe always approaches the analysis and the scientific discovery process from a structural biology perspective. Supporting the Duke Center for HIV Structural Biology (DCHSB), Dr. Wiehe will conduct antibody sequence analysis for antibodies used in computational and molecular modeling analyses conducted.
Garnett H. Kelsoe
- Lymphocyte development and antigen-driven diversification of immunoglobulin and T cell antigen receptor genes.
2. The germinal center reaction and mechanisms for clonal selection and self - tolerance. The origins of autoimmunity.
3. Interaction of innate- and adaptive immunity and the role of inflammation in lymphoid organogenesis.
4. The role of secondary V(D)J gene rearrangment in lymphocyte development and malignancies.
5. Mathematical modeling of immune responses, DNA motifs, collaborations in bioinformatics.
6. Humoral immunity to influenza and HIV-1.
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