Peter Burrows, Ph.D.
We are interested in the development of B lymphocytes and their subsequent antigen-dependent differentiation into effector cells. Immunoglobulin (Ig) gene rearrangements, as well as a number of essential changes in gene expression, take place as cells progress through this differentiation pathway. Our laboratory has been using both cellular and molecular approaches to characterize precursors of human B lineage cells and to identify novel genes whose expression is developmentally regulated. One new subfamily of genes that we have identified encodes proteins with homology to the Fc receptors for immunoglobulins (FcR). The two members of this family, FCRLA and FCRLB differ from previously identified FcR and other FcR-like (FCRL) molecules in that they are intracellular proteins. We have recently shown that FCRLA is a resident endoplasmic reticulum protein that binds Ig in this organelle. In striking contrast to the conventional plasma membrane FcRs, FCRLA binds multiple isotypes of Ig, IgM, IgG, and IgA. We are currently testing the hypothesis that FCRLA is important in the initial metabolism of Ig in B cells and thus in normal immune system function. Our findings thus far suggest a novel role for this protein in Ig assembly or degradation. Defects in human FCRLA expression may thus lead to autoimmunity or immunodeficiency diseases.
Hui Hu, Ph.D.
One of the major research projects in the Hu laboratory is to study Tfh cell differentiation and germinal center (GC) responses. The humoral immune response is one of the two effector arms of the immune system. Studies have shown that CD4+ T follicular helper (Tfh) cells are essential for long-lived, high affinity antibody responses. Yet the complex regulation that determines the initial development of Tfh cells, their developmental progression in germinal centers, and their fates after an immune response dissolves, is still not fully understood. The Hu laboratory is interested in identifying novel pathways underlying the differentiation of Tfh cells in humoral responses and designing new strategies to manipulate humoral responses for treatment of infectious diseases and autoimmune disorders. Recently the Hu laboratory has discovered that transcription factor Foxp1 is a rate-limiting and essential negative regulator of Tfh cell differentiation, drastically affecting GC and antibody responses (Nat. Immunol. 2014).
The Hu laboratory is also working to find ways to activate T cells under immunosuppressive circumstances. Much of the understanding of molecular mechanisms regulating immune responses is centered on pathways and processes that promote cell activation, division and differentiation. The Hu laboratory has demonstrated that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state (Nat. Immunol. 2011). If these pathways are disrupted, resting T cells become aberrantly activated even in the absence of antigen challenge. The Hu laboratory is interested in identifying regulatory genes and pathways that actively restrain T cell activation, and defining the roles of such negative regulatory pathways in controlling T cell quiescence, effector responses, memory maintenance, and tumor immunology.
Louis B. Justement, Ph.D.
Ongoing studies in the laboratory focus on elucidation of molecular mechanisms that control the T-dependent as well as the T-independent humoral immune response. Projects in the laboratory focus on a range of specific processes that relate to; 1) maintenance and function of the marginal zone in the spleen and responses to blood borne pathogens, 2) initiation and maintenance of the germinal center reaction following challenge with T-dependent antigens, 3) the role of CD19 in regulating the duration of the primary humoral response and the formation of memory, and 4) the role of the adaptor protein HSH2 in regulating immunoglobulin class switching and terminal differentiation in response to T-independent and T-dependent antigens. A common theme for all of the projects listed above is the analysis of intracellular signaling processes that promote B cell activation, survival and differentiation. The laboratory has a long-standing interest in structure/function analysis of co-receptors on B cells, including CD45 and CD22. More recently, the laboratory has become interested in determining the functional role of the B cell co-receptor CD19 in regulating the primary humoral response and the generation of memory B cells through the use of transgenic mouse lines that express CD19 with specific mutations in cytoplasmic tyrosine residues. Studies focused on an analysis of the molecular mechanisms by which the adaptor protein HSH2 regulates B cell class switching utilize mouse models in which HSH2 expression has been modulated in the B cell lineage. Studies have determined that this adaptor functions downstream of TNFR family members and modulates distal signaling events important for terminal B cell differentiation. Studies related to marginal zone and germinal center biology focus on the cross-talk between different receptor types in trans that promote proper cellular development and function and rely on a wide range of knockout and transgenic mouse lines. Additionally, studies are ongoing to characterize the expression and function of the TREM locus receptor TREM-Like Transcript 2 (TLT2). TLT2 is expressed on cells that play a role in the innate and adaptive immune responses and has been shown to potentiate cellular responses to a range of agonists that signal via G protein-coupled receptors. Thus, TLT2 is thought to play a critical role in regulating immune cell migration and trafficking, as well as activation. Studies pertaining to TLT2 are focused on delineation of the molecular mechanisms by which TLT2-mediated signaling affects the host response to fungal and bacterial pathogens, as well as its role in mediating acute inflammation.
Masa Kamata, Ph.D.
The major research foci of our laboratory are understanding a) how viruses or malignant cells establish and maintain prolonged infections or uncontrolled cell division, respectively, in patients under host immune pressure and b) how the host immune system can be mobilized to fight infection or cancer. To this end, we have worked to establish effective strategies using humanized mouse and non-human primate models; our aim is to develop a treatment capable of achieving a state wherein the host immune system decreases levels of virus or cancer in patients to the point where further treatment is not necessary. Our recent efforts using immunotherapeutic strategies have provided potential tools for controlling HIV-1 load as well as aggressive cancers that metastasize to the brain. These studies provide fundamental insight into the basis of host-virus and host- malignant cell interactions and ultimately identify clinically relevant therapeutic targets to augment immune responses and restore antiviral or anticancer immunity in patients.
John F. Kearney, Ph.D.
The overall research plans of the Kearney laboratory are aimed at discovering fundamental cellular and molecular mechanisms involved in the development of T and B lymphocytes. Particular attention is focused on the factors involved in the establishment of a diverse B cell repertoire and the identification of novel B cell subsets and B cell progenitors. This basic research is then applied to immune responses to the pathogens and opportunistic pathogens (Bacillus anthracis, Streptococcus pneumoniae, groups A and B streptococci, Enterobacter cloacae, Aspergillus fumigatus) thus leading to studies on mechanisms of disease in mouse models.
A major portion of the Kearney laboratory research addresses the “hygiene hypothesis” that links the increase in autoimmune and allergic phenomena including Type 1 diabetes and allergic asthma in humans to excessively sanitary conditions provided to our children early in life. These are significant public health problems worldwide, associated with an alarming decrease in the age of onset. A particular focus is on the role of antibodies to these organisms with the potential to dampen allergic and autoimmune diseases.
The objective of our work on autoimmune diabetes is based on the observations that (i) childhood infection with Group A strepococci that causes Scarlet fever has a negative impact on T1D development in humans and (ii) a similar effect is observed in rodent models. Antibodies are important in fighting infections but multiple studies now show that certain antibodies have housekeeping functions, in that they can clean up and dispose of dead or dying cells in our body. Our preliminary studies suggest that this novel approach will be effective in preventing the development of T1D by inducing long-term antibody production to self-antigens in beta islet cells without interfering with other immune functions. Our idea is that these antibodies will divert autoantigens into pathways that block or dampen the production of T lymphocytes with the potential to destroy insuIin-producing beta islet cells in the pancreas. Our goal is to develop a strategy that will provide a possible therapeutic or vaccination option for treatment or prevention of T1D. Antigen-based therapies to induce T cell tolerance use a single antigen whereas our approach has the potential to dampen autoimmunity against known or ignored determinants of beta cell secretory granules, and prevent spreading of anti-islet cell activity and inhibit late stage T1D.
Asthma is a potentially life threatening chronic respiratory disease, which is an increasingly significant public health problem worldwide. In the United States 16.4 million non-institutionalized adults and 7.0 million children currently have asthma, accounting for 7.3% and 9.4% of these total populations, respectively. The “hygiene hypothesis” links the increasing allergic airway diseases to lack of appropriate microbial exposure early in life. A single neonatal immunization of mice with a Group A streptococcal vaccine induces antibodies that are sustained well into adulthood and protect against airway allergic responses. Base on these findings we are investigating new therapeutic or vaccination options in mouse models of allergic airways disease for the prevention/treatment of allergic asthma.
Fungal infections involving opportunistic pathogens have increased dramatically in the last 20 yrs. due mainly to increased numbers of HIV patients, and severe immunosuppressive regimens involved in a variety of therapies such as bone marrow transplants and chemotherapy. The lack of effective vaccines and the emergence of strains resistant to effective anti-fungal agents have compounded the significance of this health problem that has a very high morbidity. We have shown that targeting antibodies to shared components of bacterial and fungal species elicit protective antibody responses to fungal infections in mice. Our ongoing studies on anti-fungal immunity revolve around identification of protective antibody to novel vaccine targets on Candida albicans and Aspergillus fumigatus.
Rodney King, Ph.D.
Dr. King has a long standing interest in B cell biology, specifically the factors that influence the production of their principle effector molecules, antibodies, and the role of these molecules in health and disease. More recently, he has focused on the analysis of glycan-specific B cell repertoire formation and the development of methodologies to facilitate the expression of recombinant antibody derived from the antigen receptor genes of single-sorted B cells. His current focus is on visualizing effects of environmental influences and commensal organisms on natural repertoire development in mice and humans and utilizing the constituents of these highly conserved glycan-specific repertoires to develop diagnostic and therapeutic reagents.
Christopher A. Klug, Ph.D.
Our laboratory has had a longstanding interest in understanding the genetic control of hematopoietic stem cell (HSC) differentiation into the earliest committed lymphoid cells in the bone marrow. This process is mediated by a number of factors including transcription factors and growth factor signaling pathways that both promote lineage specification as well as repress differentiation into alternative blood cell fates. Differentiation of HSC is also coupled with maintenance of the stem cell state in a process called self-renewal, which effectively maintains homeostasis within the hematopoietic system throughout life. Some of our ongoing work has focused on the characterization of murine and human mesenchymal stem cells (MSC), which form part of the HSC niche, for their ability to promote HSC self-renewal. This work has implications for expansion of HSC in vitro and for promotion of graft facilitation during bone marrow transplantation.
Frances Lund, Ph.D.
The overarching research objective of the Lund laboratory is to identify the key players that suppress or exacerbate mucosal immune responses with the long-term goal of developing therapeutics to treat immunopathology associated with chronic infectious, allergic and autoimmune disease. To evaluate inflammation and cellular immune responses in vivo, we utilize different strains of mice that have genetically altered immune systems. In particular, we focus on evaluating mice that have alterations in the B lymphocyte compartment. We expose these mice to pathogens, allergens or autoantigens and then study the ensuing immune responses in lymphoid organs and in mucosal tissues like the lung and gut. We study immune responses in mice that spontaneously develop autoimmune diseases like Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) or Type 1 Diabetes (T1D). We also examine inflammatory and immune responses in mice exposed to common allergens like house dust mite or infected with viral (influenza, RSV), bacterial (Streptococcus pneumoniae, Listeria monocytogenes), fungal (Pneumocystis carinii) or parasitic (Heligmosomoides polygyrus) pathogens. Finally, we expose mice to toxins like cigarette smoke and DNA-damaging chemotherapeutics and monitor chronic inflammation and tissue damage in sites such as the lung.
Jiri Mestecky, M.D., Ph.D.
Our group has been involved for an extended time period in the studies of various aspects of mucosal immunology such as the polypeptide chain and glycan structures of secretory IgA antibodies, including the independent discovery of J chain. In parallel, cellular aspects of IgA biosynthesis, catabolism, and selective transepithelial transport have been investigated. We have demonstrated the cellular and tissue origins of various molecular forms of IgA (monomeric/polymeric of IgA1 and IgA2 subclasses)and determined tissue sites, cell types, and receptors involved in IgA binding and catabolism using various animal models and isolated cells. In collaboration with other members of the mucosal immunology group we studied the induction of humoral and cellular immune responses in mucosal sections and tissues and we provided direct evidence for the existence of the common mucosal immune system in humans. Various mucosal immunization routes, antigen delivery systems and adjuvants have been compared with respect to the magnitude, duration, and quality of immune responses induced at desired mucosal sites.
More recent studies have been focused on the impact and immune response induced by HIV infection or immunization with experimental vaccines. In parallel, studies of molecular defects and regulation of glycosylation of IgA1 isolated from sera of patients with the most common glomerulonephritis in the world – IgA nephropathy – led to the discovery of the molecular basis of this disease and characterization of nephritogenic immune complexes.
Suzanne Michalek, Ph.D.
We are interested in the mucosal and innate immune systems; the development of mucosal vaccines against microbial pathogens; cellular mechanisms engaged following microbial-host interaction, e.g., signaling pathways activated, that could lead to the development of immunotherapeutics.
Jan Novak, Ph.D.
Dr. Novak’s research interests in Immunology include glycoimmunobiology and glycoimmunopathology as they relate to structure and function of antibodies and other glycoproteins in health and disease and possible interventional approaches for treatment of diseases. Major topics are related to renal diseases and autoimmune diseases (IgA nephropathy and other chronic diseases of the kidney), cancer, and mucosal infections, including sexually transmitted diseases, such as those caused by HIV.
Carlos J Orihuela, Ph.D.
The Orihuela laboratory examines the host-pathogen interactions that occur during invasive pneumococcal disease. This includes dissecting at a molecular level how Streptococcus pneumoniae virulence determinants interact with the host, how the host cell responds to infection at the cell signaling level, and how these interactions change with advanced age. Currently the Orihuela laboratory is exploring the new observation that S. pneumoniae invades the heart and causes long-lasting cardiac damage during pneumonia. Specific topics that are being investigated include necroptosis, a pro-inflammatory cell death pathway, involved in pneumolysin-mediated killing of monocytes and cardiomyocytes, how inflamm-aging enhances permissiveness for bacterial infection through upregulation of homeostatic suppressors meant to keep sterile inflammation under control, and the host response to different bacterial phenotypes during its growth within an infected heart.
Mark R. Walter, Ph.D.
Role of Interferons and other cytokines in Lupus: The type I interferon family (IFNs) consists of 15 different molecules that have diverse functions such as activating cells to control viral infections. However, the IFNs also play a pathogenic role in an autoimmune disease called systemic lupus erythematosus (SLE). The IFNs have been implicated in the initiation and worsening of the disease, most notably in kidney damage (lupus nephritis). The Walter lab is designing molecular tools to measure IFN levels in the blood and kidneys of lupus patients. The project is expanding to evaluate how other cytokine pathways intersect with the IFNs in disease progression. The results of these studies may be used to monitor disease and/or choose the appropriate therapy to improve patient health. This is a collaborative project between clinicians and biochemists motivated to understand how to prevent and/or manage the devastating impact of lupus on people’s lives.
Design of novel vaccines against human cytomegalovirus (HCMV): Current viral vaccines elicit antibodies to viral proteins that prevent or limit entry of virus into cells of their host. To date, this strategy has not been successful in a number of viruses, including HCMV, that directly target immune cell signaling pathways to evade host immune responses. HCMV infection can cause severe hearing loss, mental disabilities, and even death in a developing fetus (For more information see this link). Currently there is no vaccine for HCMV. To address this problem, we are using our expertise in cytokine structural biology to design novel antigens that target virally produced cytokines. To date, these antigens show efficacy in animal models of HCMV. Further testing of this strategy and evaluating molecules for possible clinical trials are now underway. See
1. Logsdon et al. Design and Analysis of Rhesus Cytomegalovirus IL-10 Mutants as a Model for Novel Vaccines against Human Cytomegalovirus. PLoS One. 6 (2011).
2. Eberhardt et al. Host Immune Responses to a Viral Immune Modulating Protein: Immunogenicity of Viral Interleukin-10 in Rhesus Cytomegalovirus-Infected Rhesus Macaques. PLoSOne 7 (2012).
Allan J. Zajac, Ph.D
I love studying cell-mediated immune responses to infections. My research program is centered upon understanding why robust and highly effective immune responses are induced by certain viral infections and vaccinations and why and how they become corrupted during persistent infections, compromising viral control. Our studies have shown that virus-specific CD8 T cells succumb to exhaustion during persistent infections, and have highlighted a vital role for CD4 T cells in supporting CD8 T cell responses. We also discovered that the CD4 T cell-derived cytokine, IL-21, is essential for sustaining cell-mediated immunity in chronically infected hosts. More recently, we demonstrated that adhesion molecule interactions influence the balance of effector and memory phenotype cells, and also regulate the deletion of virus-specific CD8 T cells during chronic infections. As our projects have advanced a common immunological theme that has emerged is the central role of cytokines, as both intrinsic regulators and predictors of the outcome of the CD8 T cell response, and also as extrinsic factors that provoke and direct their development. Consequently, our interests have evolved towards analytically deconvoluting the functional complexity of CD8 T cell responses, with a major goal of understanding how the formation of discrete cytokine-producing subsets is controlled and how they contribute to the clearance of infections and tumors. These studies are helping to define how CD8 T cell functional disparities translate to qualitative and quantitative differences in the ensuing response, forecast fate decisions, and dictate protective efficacy.