Spatiotemporal Dynamics of Immune Regulation
Overview
Our immune system is a dynamic and powerful network of cells and molecules that constantly protect us from pathogens. During an immune response, information about pathogen/tissue damage is quickly relayed to the nearest lymphoid organs. Fast-moving lymphocytes constantly scan lymphoid organs for specific signals displayed on antigen-presenting cells. Once lymphocytes recognize their antigens, they proliferate, differentiate into specialized effector cells, exit the lymphoid organs, and migrate to target tissues to execute effector functions (e.g., clear pathogens). Immune responses are exquisitely regulated to ensure targeted clearance of pathogens while avoiding misfiring against self-tissues (e.g., autoimmunity). The fundamental biological processes orchestrating immune responses are generally hidden from view and operate at multiple scales in both space and time. Space: The spatial scale at which immune processes take place varies from centimeters (tissue organization) to millimeters (local cell patterns) and micrometers (cell-cell interactions). Time: Cellular landscapes of tissues change within hours due to cell-cell interactions that last several minutes, triggering molecular signaling events lasting a few microseconds to several seconds. Therefore, Our research aims to uncover the spatial and temporal dynamics of immune responses in physiological settings using a combination of advanced multiphoton imaging of fluorescently tagged cells, fate-mapped reporters, and functional genetics in animal models of autoimmune encephalomyelitis, orthotopic tumors, and vaccine responses. We are capitalizing on our recent Ca2+ probe Salsa6f, for live readout of immune cell activation states. In addition, autofluorescence lifetime imaging to measure metabolic states (e.g., NADH) of selected immune cells in living tissues; and label-free imaging of myelin (THG) and collagen (SHG) will reveal new insights into immune regulation in various contexts. In the long term, we seek to broaden our understanding of how immune cells work in vivo and execute essential functions in human health and diseases. Our research will aid in developing new therapeutic strategies for infectious diseases, autoimmune disorders, organ transplantation, and solid tumors. Current research programs are summarized below.
1) Neuroimmunology
Although regulatory T (Treg) cells constantly prevent autoimmune diseases and orchestrate tissue repair pathways, our understanding of how they function locally in the target tissues is still incomplete, particularly in the central nervous system (CNS). The neuroimmunology research program aims to study the cellular and molecular mechanisms of Treg cells during autoimmune neuroinflammation using Multiple Sclerosis (MS)-like disease model in mice. Our recent work shows that recovery from autoimmune neuroinflammation is contingent on Treg cells . Treg cells in the CNS form local niches and display a unique repetitive-scanning motility behavior, often re-engaging the same antigen presenting cell (APC). Our studies will illuminate how Treg cells resolve neuroinflammation (CNS autoimmunity) and promote neuronal repair pathways (remyelination).
Goal
Uncover tissue-specific mechanisms of regulatory T cells in the CNS to prevent and treat autoinflammatory/neurodegenerative disorders.
Impact
Our studies will define how Treg cells selectively target processes that incite neuroinflammation and uncover molecular pathways for selective remyelination of denuded axons in MS and lay the foundation for tissue repair potential of Treg cells for other neurodegenerative diseases (e.g., Alzheimer’s ).
Relevant Publications
https://pubmed.ncbi.nlm.nih.gov/?term=Othy+Treg+cells&show_snippets=off&sort=date&size=20
2) Mechanoimmunology
We have recently defined the role of mechanically-activated Piezo1 channels in helper T (CD4) cell functions. However, the role of Piezo1 channels in cytotoxic (CD8) T-cell functions is entirely unknown. The objective mechanoimmunology research program is to investigate how Piezo1 channels modulate the tissue-homing capacity, interstitial motility, activation, proliferation, cytokine production, and direct killing function of CD8 T cells. This is important because CD8 T cells experience complex mechanical cues as they actively probe the surface of other cells, navigate barriers, squeeze through interstitial spaces, and execute direct killing of target cells in tissues. Moreover, tissue stiffness poses a unique challenge for CD8 T cells (e.g., tumor penetration and survival in stiff tissues).
Goal
Decode mechanosensing in Cytotoxic T lymphocytes to fight solid tumors and chronic inflammation.
Impact
These studies will uncover the role of mechanical signals in CD8 T cell-mediated immunity, as well as lay the foundation for the therapeutic potential of Piezo1 as a new target to potentiate anti-tumor responses.
Relevant Publications
https://pubmed.ncbi.nlm.nih.gov/?term=Othy+Piezo1+Salsa6f&show_snippets=off&sort=date&size=20
3) Vaccine Biology
Developing an effective vaccine for novel viruses is challenging because our understanding of how vaccines work is still incomplete. Specifically, the biological processes underscoring protective immunity are hidden from view. Safe and effective vaccines are made from purified antigens instead of whole pathogens, but these require adjuvants. Combining multiple adjuvants to mimic natural viral infection increases vaccine efficacy over single adjuvants. However, the immunological processes triggered by adjuvant combinations leading to long-term adaptive immunity are not well defined. The objective of the vaccine biology research program is to determine how combinations of adjuvants effectively activate innate and adaptive immune cells. We are investigating critical steps of antigen delivery, cellular choreography, and lymphocyte activation events leading to adequate immunization using multiphoton microscopy.
Goal
Identify cellular and molecular mechanisms of adjuvant combinations that elicit robust protective immunity
Impact
Our studies will serve as a foundational basis to optimize adjuvant combinations for the ideal programming of immune responses against infectious diseases & future pandemics
Relevant Publications
https://pubmed.ncbi.nlm.nih.gov/?term=Davies+DH+adjuvant&show_snippets=off&sort=date&size=20
