Igyártó Research
Contact
233 South 10th Street
620 BLSB
Philadelphia, PA 19107
The research in the Igyártó laboratory is centered around understanding dendritic cell (DC) biology and developing effective DC vaccines for infectious diseases, autoimmune diseases, allergy, and cancer. Many innovative projects are going on in the lab, only a few of which are highlighted below. Please reach out to us if you are hungry for more.
Highly motivated post-docs interested in joining the lab should contact the PI directly.
Research Projects
Intracellular monitoring by dendritic cells
DC (CFSE-labeled) stretches dendrites into neighbor KC
Conventionally, dendritic cells are thought to acquire antigen for presentation by either scavenging extracellular material or by becoming infected. However, our lab recently demonstrated that dendritic cells in the epidermis acquire cellular material directly from the cytosol of surrounding keratinocytes, likely by using a combination of nanotubes and dendrites. This process, that we call intracellular monitoring/surveillance, enables the transfer of mRNA and other molecules, and allows dendritic cells to collect real time information on the intracellular niche of surrounding cells. We are working to identify the exact mechanism of transfer, and understand its potential role in self-tolerance, antigen presentation, intercellular communication, and immunosurveillance.
DCs (Red) are taking up internal materials from KC (Green).
Determine how different DC subsets regulate humoral immune responses
DCs are professional antigen-presenting cells (APCs) that regulate all aspects of the adaptive immune response. However, our knowledge is very limited to how DC subsets regulate humoral immune responses (antibody responses). Since many vaccines’ effectiveness relies on the induction of neutralizing antibody (humoral) responses, understanding the mechanism by which DC subsets regulate humoral immune responses is crucial for the development of more effective vaccines. In this project, we aim to determine the mechanistic aspects of DC-regulated humoral immune responses.
Sequential activation model. Based on this model the Langerhans cells (LCs) first initiate the differentiation of Tfh cells and then licensed by the Tfh cells migrate into the B cell area to deliver the intact antigen for B cell activation. The B cells then interact with the Tfh cells to promote their final maturation and in turn the B cells will differentiate into plasma cells and memory cells. The responses induced by LCs could be inhibited by high antigen dose and IL-10. We also discovered that cDC1s can prevent LCs from inducing humoral immune responses. The cDC1s were not able to drive significant humoral immune responses in steady state, but inflammatory signals enabled them.
How the absence of immune cells affects tissue homeostasis?
The effect of tissue environment on immune cells has been widely studied. It is well-documented that keratinocytes can regulate the immune response by affecting epidermal-resident, antigen-presenting Langerhans cell biology through secretion of cytokines and other factors. However, it is unknown whether the long-term absence of immune cells could affect the tissue homeostasis. We found that the long-term lack of epidermal resident Langerhans cells led to significant gene expression changes in the local keratinocytes and resident dendritic epidermal T cells. Thus, immune cells might play an active role in maintaining tissue homeostasis, which should be taken into consideration at data interpretation.
One-step artificial APC for cancer immunotherapy and not just
The production and wide use of artificial antigen-presenting cells (aAPCs) in the clinic as cancer immunotherapeutics are hindered by the need for identifying immunogenic cancer antigens and production of recombinant patient-specific major histocompatibility complexes (MHC) loaded with these peptides. To overcome these limitations, we tested the idea of whether peptide-MHCs can directly be captured from cell lysates, including cancer cells using affinity beads, and used to initiate T cell responses. In theory, these affinity beads covered with the unknown peptide-MHC repertoire captured from the cancer cells could interact with a wide range of antigen-specific T cells and promote anti-cancer responses. Indeed, we found that we can successfully pull-down peptide-MHCs from cell lysates and the aAPCs generated using this technique were able to induce antigen-specific cytotoxic effector T cell responses that led to in vitro and in vivo tumor cell killing. In summary, we present here a novel technique to generate patient-specific aAPCs, that might have the potential to revolutionize the field of cancer vaccines and provide patients with a vaccine in matters of days at minimal costs.
Graphical representation of one-step aAPC generation. Tumor cell lysates are incubated with affinity beads that capture the peptide-MHC-I repertoire of the cancer cells. The beads are then used to activate cancer antigen-specific T cell clones that will ultimately kill the tumor cells.
Determine the immune mechanism of the mRNA vaccines and identify the drivers of the side effects
The mRNA-LNP vaccine platform has gained much attention with the ongoing SARS-CoV-2 pandemic. Millions of people are exposed to these vaccines daily, but their immune mechanism driving the antibody responses and side effects remains unexplored. Our recent work reported that Acuitas LNPs' ionizable lipid component used in preclinical nucleoside-modified mRNA vaccine studies is highly inflammatory in mice. Thus, the mRNA-LNP platforms' potency in supporting the induction of adaptive immune responses and the observed side effects likely stem from the LNPs' highly inflammatory nature. We also showed that this platform could support protective immune responses in the absence of some innate immune cells (specific DC subsets and neutrophils) and cytokines (IL-6). We are now on the quest to determine how the highly inflammatory nature of this platform and its long in vivo half-life affects subsequent immune responses.