Papers by Irina Grigorova
C33. INFLAMMATORY MODULATION IN SARCOIDOSIS, LUNG TRANSPLANT, AND OTHER DISEASES, May 1, 2022
Journal of Immunology, May 1, 2021
Follicular regulatory T cells (Tfrs) have been reported to play multiple roles in the control of ... more Follicular regulatory T cells (Tfrs) have been reported to play multiple roles in the control of B cells response. They repress foreign antigen-specific germinal center (GC) B cells at the peak of GC response. At the same time, under some conditions they promote GC B cell cycling in IL-10 dependent fashion and ensure optimal affinity maturation. Our previous studies suggested that CCL3 produced by GC centrocytes (CCs) promoted their direct contacts with Tfr cells and negative regulation of GC B cells at the peak of GC response. However, which fraction of CCs upregulates CCL3 expression, which receptors on Tfrs may respond to CCL3, and the long-term effect of CCL3 on GCs has been unclear. Based on the single cell and bulk qPCR analysis we found that CCL3 is upregulated in about 10% of CCs that express Myc and are undergoing positive selection. qPCR and transwell analysis revealed expression and synergistic involvement of CCR5 and CCR1 chemokine receptors on Tfr cells in their chemotaxis to CCL3. Interestingly, both an adoptive transfer and mixed bone marrow chimeras models suggest that after the peak of GC response B cell-intrinsic production of CCL3 promotes their prolonged participation in GCs and B cell affinity maturation, as well as better memory and plasmablast response. We also showed that both the negative and positive regulation of GC B cells by CCL3 was dependent on the presence of Tregs. To summarize, our studies suggest that in addition to the role of CCL3 and Tregs in the modest repression of foreign antigen-specific B cells at the peak of GC response, it is also important for optimal selection of B cells in GCs. Further studies are underway to determine the role of Tfr cells specifically in the negative and positive CCL3-mediated regulation of GCs.
bioRxiv (Cold Spring Harbor Laboratory), Oct 27, 2022
We thank Prof. Jason Cyster (UCSF) for useful discussions and comments on the manuscript. Single ... more We thank Prof. Jason Cyster (UCSF) for useful discussions and comments on the manuscript. Single cell processing and next-generation sequencing was carried out in the Advanced Genomics Core at the University of Michigan.
Journal of clinical & cellular immunology, Nov 8, 2017
Journal of clinical & cellular immunology, Oct 15, 2015
Journal of Immunology, Jun 8, 2018
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by increased type I int... more Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by increased type I interferons (IFNs), autoantibodies, and inflammatory-mediated multi-organ damage. TLR7 activation is an important contributor to SLE pathogenesis, but the mechanisms by which type I IFNs participate in TLR7-driven pathology remain uncertain. In this study, we examined the requirement for type I IFNs in TLR-7 stimulated lupus nephritis. Lupus-prone NZM2328, INZM (which lack a functional type I IFN receptor), and NZM2328 IL-1β−/− mice were treated at 10 weeks of age on the right ear with R848 (TLR7 agonist) or control (DMSO). Autoantibody production and proteinuria were assessed throughout treatment. Multi-organ inflammation was assessed at the time of decline in health. Renal infiltrates and mRNA expression were also examined after 14 days of treatment. Both NZM2328 and INZM mice exhibited a decline in survival after 3-4 weeks of R848 but not vehicle treatment. Development of splenomegaly and liver inflammation were dependent on type I IFN. Interestingly, autoantibody production, early renal infiltration of dendritic cells, upregulation of IL-1β, and lupus nephritis occurred independent of type I IFN signaling. Development of TLR7-driven lupus nephritis was not abolished by the deletion of IL-1β. Thus, while IFNα is sufficient to induce nephritis acceleration, our data emphasize a critical role for IFN-independent signaling in TLR7-mediated lupus nephritis. Further, despite upregulation of IL-1β after TLR7 stimulation, deletion of IL-1β is not sufficient to reduce lupus nephritis development in this model.
International Immunology
Follicular regulatory T (Tfr) cells play various roles in immune responses, contributing to both ... more Follicular regulatory T (Tfr) cells play various roles in immune responses, contributing to both positive and negative regulation of foreign antigen-specific B cell responses, control over autoreactive antibody responses and autoimmunity, and B cell class-switching to IgE and allergy development. Studies conducted on mice uncovered various subsets of CXCR5+FoxP3+CD4+ Tfr cells that could differently contribute to immune regulation. Moreover, recent studies of human Tfr cells revealed similar complexity with various subsets of follicular T cells of different origins and immunosuppressive and/or immunostimulatory characteristics. In this review we will overview and compare Tfr subsets currently identified in mice and humans and will discuss their origins and antigen specificity, as well as potential modes of action and contribution to the control of the autoimmune and allergic reactions.
Activation of CD8+T cells against pathogens and cancers involves the recognition of antigenic pep... more Activation of CD8+T cells against pathogens and cancers involves the recognition of antigenic peptides bound to human leukocyte antigen (HLA) class-I proteins. Peptide binding to HLA class I proteins is coordinated by a multi-protein complex called the peptide loading complex (PLC). Tapasin, a key PLC component, facilitates the binding and optimization of HLA class I peptides. However, different HLA class I allotypes have variable requirements for tapasin for their assembly and surface expression. HLA-B*44:02 and HLA-B*44:05, which differ only at residue 116 of their heavy chain sequences, fall at opposite ends of the tapasin-dependency spectrum. HLA-B*44:02 (D116) is highly tapasin-dependent, whereas HLA-B*44:05 (Y116) is highly tapasinindependent. Mass spectrometric comparisons of HLA-B*4405 and HLA-B*44:02 peptidomes were undertaken to better understand the influences of tapasin upon HLA-B44 peptidome compositions. Analyses of the HLA-B*44:05 peptidomes in the presence and absenc...
The Journal of Immunology
Expression of CCL3 and CCL4 chemokines is upregulated in B cells upon crosslinking of B cell rece... more Expression of CCL3 and CCL4 chemokines is upregulated in B cells upon crosslinking of B cell receptors and in germinal center (GC) centrocytes. However, the role of these proinflammatory chemokines in B cell responses is still unclear. Single cell qPCR analysis suggests that only a small fraction of GC centrocytes upregulates expression of CCL3/4. While B cell-intrinsic production of CCL3 promotes B cell interactions and negative control by follicular regulatory T cells at the peak of GC response, at the later stages of GC response it promotes B cells selection. Consistent with that, secondary antibody responses in CCL3 knockout mice are reduced. Our findings suggest that CCL3 is involved into multifaceted regulation of GC responses. Analyses of the mechanisms promoting both the negative and positive regulation of GC B cells in CCL3-dependent fashion are underway. These studies should be important for dissecting the role of CCL3 in normal immune responses and in B cell-originated ly...
Nature Immunology, 2009
In the version of this article initially published, two panels in Figure 9a were horizontally inv... more In the version of this article initially published, two panels in Figure 9a were horizontally inverted. The error has been corrected in the HTML and PDF versions of the article.
Systems Biology and Physiology Reports, 2021
COVID-19 pandemics triggered by the SARS-CoV-2 virus have caused millions of deaths worldwide and... more COVID-19 pandemics triggered by the SARS-CoV-2 virus have caused millions of deaths worldwide and have led to expedited developments of various effective vaccines that, if administered, could prevent and/or circumvent the infection and reduce the death toll. Since the start of the pandemics multiple research groups around the world have been involved in the analysis of immune responses of various human cohorts to the SARS-CoV-2 infection and vaccines. Now, over 1.5 years later, the scientific community has accumulated extensive data about both the development of an immune response to SARS-CoV-2 following infection, as well as its rate of fading off. Kinetic analysis of the immune response generated by vaccines is also emerging, enabling the possibility of making comparisons and predictions. In this review we will focus on the comparing B cell and antibody immune responses to the SARS-CoV-2 infection as opposed to mRNA vaccines for the SARS-CoV-2 S-protein, which have been utilized to immunize hundreds of millions of people and analyzed in multiple studies.
Immunological Reviews, 2020
Bretcher and Cohn's two-signal hypothesis of lymphocyte activation predicts that antigen (Ag) rec... more Bretcher and Cohn's two-signal hypothesis of lymphocyte activation predicts that antigen (Ag) receptor signaling alone is insufficient for full activation of lymphocytes and their differentiation into effector cells. 1,2 While highly crosslinking-Ags, for example, bacterial capsular polysaccharides and repetitive motifs in viral capsids, induce prolonged and persistent B cell receptor (BCR) signaling in B cells that can bypass the requirement of secondary signals, 3-5 in most physiological settings the "second signal" is necessary for B cell proliferation and differentiation into antibody (Ab)-secreting plasma cells (PCs). These signals may be provided by various molecular factors and cellular sources. 6 B cell responses that require secondary, contact-dependent (cognate) signals from helper T cells (Th) are called T-dependent. T-independent responses encompass all other scenarios that trigger B cell proliferation and differentiation into PCs.
Nature Communications, 2020
Macropinocytosis is an evolutionarily-conserved, large-scale, fluid-phase form of endocytosis tha... more Macropinocytosis is an evolutionarily-conserved, large-scale, fluid-phase form of endocytosis that has been ascribed different functions including antigen presentation in macrophages and dendritic cells, regulation of receptor density in neurons, and regulation of tumor growth under nutrient-limiting conditions. However, whether macropinocytosis regulates the expansion of non-transformed mammalian cells is unknown. Here we show that primary mouse and human T cells engage in macropinocytosis that increases in magnitude upon T cell activation to support T cell growth even under amino acid (AA) replete conditions. Mechanistically, macropinocytosis in T cells provides access of extracellular AA to an endolysosomal compartment to sustain activation of the mechanistic target of rapamycin complex 1 (mTORC1) that promotes T cell growth. Our results thus implicate a function of macropinocytosis in mammalian cell growth beyond Ras-transformed tumor cells via sustained mTORC1 activation.
The Journal of Immunology, 2019
Epitope density has a profound impact on B cell responses to particulate Ags, the molecular mecha... more Epitope density has a profound impact on B cell responses to particulate Ags, the molecular mechanisms of which remain to be explored. To dissect the role of epitope density in this process, we have synthesized a series of liposomal particles, similar to the size of viruses, that display a model self-antigen peptide at defined surface densities. Immunization of C57BL/6J mice using these particles elicited both IgM and class-switched IgG1, IgG2b, and IgG3 autoreactive Abs that depended on the epitope density. In C57BL/6 gene knockout mice lacking either functional TCRs or MHC class II molecules on B cells, the liposomal particles also elicited IgM, IgG1, IgG2b, and IgG3 responses that were comparable in magnitudes to wild-type mice, suggesting that this B cell response was independent of cognate T cell help. Notably, the titer of the IgG in wild-type animals could be increased by more than 200-fold upon replacement of liposomes with bacteriophage Qb virus-like particles that displayed the same self-antigen peptide at comparable epitope densities. This enhancement was lost almost completely in gene knockout mice lacking either TCRs or MHC class II molecules on B cells. In conclusion, epitope density above a threshold on particulate Ags can serve as a stand-alone signal to trigger secretion of autoreactive and class-switched IgG in vivo in the absence of cognate T cell help or any adjuvants. The extraordinary immunogenicity of Qb viral-like particles relies, in large part, on their ability to effectively recruit T cell help after B cell activation.
Selection of germinal center (GC) B cells with B cell receptors (BCR) possessing high affinity to... more Selection of germinal center (GC) B cells with B cell receptors (BCR) possessing high affinity to foreign antigen (Ag) and their differentiation into antibody-secreting long-lived plasma cells is critical for potent long-term humoral immunity. Ag-dependent engagement of GC B cell BCR triggers Ag internalization and loading of antigenic peptides on MHCII molecules for presentation to follicular helper T cells (Tfh) and acquisition of T cell help. However, whether it also provides signals that are critical or synergistic with T cell help for GC B cell selection and differentiation in vivo is not known. Here we show that T cell help is sufficient to induce GC B cell expansion and plasmablast (PB) formation in the absence of recurrent BCR engagement with Ag. Ag-mediated BCR crosslinking on the other hand is not sufficient to promote GC B cell selection, but can synergize with T cell help to enhance the GC B cell and PB responses when T cell help is limiting.
Frontiers in immunology, 2018
Previous studies and our findings suggest upregulated expression of proinflammatory chemokines CC... more Previous studies and our findings suggest upregulated expression of proinflammatory chemokines CCL3/4 in germinal center (GC) centrocytes. However, the role of CCL3/4 for centrocyte interactions with follicular T cells and regulation of humoral immunity is poorly understood. We found that CCL3 promotes chemotaxis of Tfr cells . Two-photon imaging revealed that B cells-intrinsic production of CCL3 promotes their probing by follicular regulatory T cells (Tfr) within GCs of murine lymph nodes. Overall this study suggests that CCL3 facilitates direct interactions of foreign antigen-specific GC B cells and their negative regulation with Tfr cells .
Cell Reports, 2018
Antigen-dependent engagement of germinal center (GC) B cell receptors (BCRs) promotes antigen int... more Antigen-dependent engagement of germinal center (GC) B cell receptors (BCRs) promotes antigen internalization and presentation for follicular helper T cells. However, whether BCR signaling is critical or synergistic with T cell help for GC B cell selection or differentiation is unclear. Here, by adapting an experimental approach that enables independent delivery of BCRcrosslinking antigen or T cell help to GC B cells in vivo, we showed that T cell help was sufficient to induce GC B cell expansion and plasmablast formation. However, although BCR crosslinking could not by itself promote GC B cell selection or differentiation, it could synergize with T cell help to enhance the GC and plasmablast responses when T cell help was limiting. These findings indicate that GC B cells can integrate variable inputs from T cell help and BCR signaling in vivo for an optimal process of selection and differentiation, critical for potent long-term humoral immunity.
The Journal of Immunology, 2017
Modern vaccines must be designed to generate long-lasting, high-affinity, and broadly neutralizin... more Modern vaccines must be designed to generate long-lasting, high-affinity, and broadly neutralizing Ab responses against pathogens. The diversity of B cell clones recruited into germinal center (GC) responses is likely to be important for the Ag-neutralization potential of the Ab-secreting cells and memory cells generated upon immunization. However, the factors that influence the diversity of B cell clones recruited into GCs are unclear. As recirculating naive Ag-specific B cells arrive in Ag-draining secondary lymphoid organs, they may join the ongoing GC response. However, the factors that limit their entry are not well understood, and it is not known how that depends on the stage of the ongoing follicular T cell and GC B cell response. In this article, we show that, in mice, naive B cells have a limited window of time during which they can undergo Ag-driven activation and join ongoing immunizationinduced GC responses. However, preloading naive B cells with even a threshold-activating amount of Ag is sufficient to rescue their entry into the GC response during its initiation, peak, and contraction. Based on these results, we suggest that productive acquisition of Ag may be one of the main factors limiting entry of new B cell clones into ongoing immunization-triggered GC responses.
Nature Communications, 2017
The perspective that naive B-cell recognition of antigen in the absence of T-cell help causes cel... more The perspective that naive B-cell recognition of antigen in the absence of T-cell help causes cell death or anergy is supported by in vivo studies of B cells that are continuously exposed to self-antigens. However, intravital imaging suggests that early B-cell recognition of large foreign antigens may be transient. Whether B cells are tolerized or can be recruited into humoural immune responses following such encounters is not clear. Here we show that in the presence of T-cell help, single transient antigen acquisition is sufficient to recruit B cells into the germinal centre and induce memory and plasma cell responses. In the absence of T-cell help, transiently antigen-primed B cells do not undergo apoptosis in vivo; they return to quiescence and are recruited efficiently into humoural responses upon reacquisition of antigen and T-cell help.
Uploads
Papers by Irina Grigorova