Shivashankar Othy

Picture of Shivashankar Othy
Assistant Professor, Physiology & Biophysics
School of Medicine
Ph.D., Pierre and Marie Curie University - Paris, 2012, Physiology and Physiopathology
Phone: (949) 824-6754
University of California, Irvine
271B Irvine Hall
1800 Health Sciences Road
University of California Irvine
Mail Code: 4560
Irvine, CA 92697
Research Interests
Regulatory Immunity, Neuro-Immune Interactions, CNS Autoimmunity, Mechanoimmunology, Vaccine Biology, and Advanced Multiphoton Imaging.
Academic Distinctions
2003-08: Veterinary Medicine Merit Scholarship, University of Agricultural Sciences-Dharwad, India
2008-10: Research Fellowship, Indian Council of Agricultural Research, India
2008-09: Graduate Student Fellowship, National Centre for Biological Sciences-TIFR, Bengaluru, India
2009-12: Erasmus Doctoral Fellowship, European Commission
2013-16: Postdoctoral Fellowship, George E. Hewitt Foundation for Medical Research
Hewitt Foundation Postdoctoral Fellow (Michael Cahalan Lab), UC Irvine, 2013-2017
Assistant Project Scientist, Dept. of Physiology and Biophysics, UC Irvine, 2018-2022
Research Abstract
The overarching goal of our research is to uncover the principles of immune regulation at organismal, cellular, and molecular levels. Our immune system is a dynamic network of cells and molecules that constantly protect us from pathogens. 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, which are triggered by molecular signaling events lasting a few microseconds to several seconds. Therefore, we study spatial and temporal dynamics of immune responses in three relevant contexts: 1) during autoimmune encephalomyelitis in the CNS; 2) during immune homeostasis and vaccine response in the lymph nodes; and 3) during cytotoxic T cell-mediated immunity. In the long term, we seek to broaden our understanding of how immune cells play essential roles in human health and disease; and develop new therapeutic strategies for infectious diseases, autoimmune disorders, organ transplantation, and solid tumors. Current research themes in the lab are:

Neuroimmunology: Tissue-specific mechanisms of regulatory T lymphocytes in the CNS. 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 studies will illuminate how Treg cells resolve neuroinflammation (CNS autoimmunity) and promote neuronal repair pathways (remyelination). We aim to develop Treg-cell therapy to achieve selective remyelination of denuded axons (e.g., MS) and lay the foundation for the tissue repair potential of Treg cells for other neurodegenerative diseases.

Vaccine Biology: Mechanisms of combination adjuvants for robust vaccines. Safe and effective vaccines are made from purified antigens instead of whole pathogens, but these require adjuvants. Combining multiple adjuvants to mimic natural infection increases vaccine efficacy over single adjuvants. However, the mechanisms of combination adjuvants are not well defined. The biological processes underscoring protective immunity during successful vaccination are hidden from view. The vaccine biology research program aims to investigate critical steps of antigen delivery, cellular choreography, and lymphocyte activation landscapes during vaccine responses. Our studies will serve as a foundational basis to optimize adjuvant combinations for the ideal programming of immune responses against viral pathogens, as well as for cancer vaccines.

Mechanoimmunology: Role of Piezo1 channels in CD8 T cell-mediated immunity. 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). Our studies will uncover the role of mechanical signals in CD8 T cell-mediated immunity and investigate the therapeutic potential of Piezo1 as a new target to potentiate anti-tumor immunotherapies, particularly for solid tumors.
Awards and Honors
2014: Imaging the Immune System - Travel Award, SIICA, Milan, Italy.
2014: AAI Young Investigator Award, - La Jolla Immunology Conference, La Jolla.
2017: Excellence in Research Award, Dept. of Physiology and Biophysics, UC Irvine.
2018: The Ray Owen Poster Award for an outstanding postdoctoral fellow, Asilomar, CA
2019: AAI Young Investigator Award, Immunology Fair, UC Irvine.
2020: Travel Award, EMBO Symposium on Calcium Signaling, India.
2021: Outstanding Career Scientist Research Award, UCI School of Medicine (Runner-Up).
2022: Outstanding Career Scientist Research Award, UCI School of Medicine (Winner).
2022: Excellence in Leukocyte Biology Award - Early Career Scientist, Society of Leukocyte Biology.
Short Biography
Shiva Othy obtained Ph.D. in Physiology and Pathophysiology from UPMC-Paris. Pursuing his vision of studying immune regulation by direct imaging of cellular interactions, Shiva joined Prof. Michael D. Cahalan for postdoctoral studies. Shiva established a ‘multiscale immunoimaging’ approach to tackle spatial and temporal scale variation of immune responses. He studied the cellular choreography of Treg cells in the lymph nodes, spinal cord, and tumors. He also co-pioneered developing a novel ratiometric calcium indicator called ‘Salsa6f’ to visualize the real-time activation of immune cells. Salsa6f offers a powerful tool to investigate the calcium signaling in motile cells in the tissue environment. In addition to uncovering new mechanisms of regulatory T cells and discovering the role of Piezo1 channels in helper T cell functions, Shiva also established several successful collaborations at UCI departments at UCI to investigate neuro-immune interactions and vaccine biology, including the role of microglia in the hypothalamus during development; origins of hematopoietic stem cells; remyelination by neural stem cells; and calcium signaling in human iPSC-derived microglia in the context of Alzheimer’s disease.
* Denotes Equal Contribution
† Corresponding authors
Bolton, J. L., Short, A.K. *, Othy, S. *, Kooiker, C.L., Shao, M., Gunn, B.C., Beck J., Bai, X., Law S.M., Savage J.C., Lambert J.L., Belelli D., Tremblay M., Cahalan, M. D., & Baram, T. Z. 2022. Impaired developmental microglial pruning of excitatory synapses on CRH-expressing hypothalamic neurons exacerbates stress responses throughout life. Cell Reports, Mar 29;38(13):110600.
Jairaman A., McQuade A., Granzotto A., Kang Y.J., Chadarevian J.P., Gandhi S., Parker I., Smith I., Cho H., Sensi SL., Othy S., Blurton-Jones M., and Cahalan M.D. 2022.TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia. Elife, Feb 22;11:e73021.
Jairaman A.*, Othy S*., Nourse J., Dong T.X, Zavala A., Chen F., Parker I., Pathak M.M., and Cahalan M.D. 2021. Piezo1 channels restrain regulatory T cells but are dispensable for effector CD4+ T cell responses. Sci Adv, Jul 7;7(28): :eabg5859.
Marangoni, F., Zhakyp, A., Corsini M., Geels, S.N., Carrizosa, E., Thelen, M., Mani, V., Prüßmann, J., Warner, R.D., Ozga, A.J., Di Pilato, M., Othy, S., Mempel, T.R. 2021. Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop. Cell, Jul 22;184(15): :3998-4015.
Atcha H., Jairaman A., Holt J.R., Meli V.S., Nagalla R.R., Veerasubramanian P.K., Brumm K.T., Lim H.E., Othy S., Cahalan M.D., Pathak M.M., and Liu W.F. 2021. Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing. Nat Commun, May 31; 12(1):3256.
Othy S*†., Jairaman A*., Dynes J.L., Dong T.X, Tune C, Yeromin A.V., Zavala A., Akunwafo C., Chen F., Parker I., and Cahalan M.D†. 2020. Regulatory T cells suppress Th17 cell Ca2+ signaling in the spinal cord during murine autoimmune neuroinflammation., Proc Natl Acad Sci USA, Jul 30;202006895. Commentary by Prof. Stefan Feske.
Wakida N.M., Gomez-Godinez V., Li H., Nguyen J., Kim E.K., Dynes J.L, Othy S., Lau A.L., Ding P., Shi L.Z., Carmona C., Thompson L.M., Cahalan M.D., and Berns M.W. 2020. “Calcium dynamics in astrocytes during phagocytosis”. Front Bioeng Biotechnol, Aug 27; 8:912.
McIntyre L.L., Greilach S.A., Othy S., Sears-Kraxberger I., Wi B., Ayala-Angulo J., Vu E., Pham Q., Silva J., Dang K., Rezk F., Steward O., Cahalan M.D., Lane T.E and Walsh C.M. 2020. Regulatory T cells promote remyelination in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis following human neural stem cell transplant. Neurobiol Dis. Jul; 140:104868.
Hernández-Ruiz M*., Othy S*., Herrera C., Nguyen HT., Arrevillaga-Boni G., Catalan-Dibene J., Cahalan M.D., and Zlotnik A. 2019. Cxcl17-/- mice develop exacerbated disease in a T cell-dependent autoimmune model. J Leukoc Biol. May; 105(5):1027-1039.
Dong T.X*., Othy S*., Greenberg M.L., Jairaman A., Akunwafo C., Leverrier S., Yu Y., Parker I., Dynes J.L., and Cahalan M.D. 2017. Intermittent Ca2+ signals mediated by Orai1 regulate basal T cell motility. Elife, Dec 14; 6:e32417. Faculty of 1000 recommended article.
Dong T.X*., Othy S*., Jairaman A., Skupsky J., Zavala A., Parker I., Dynes J.L., and Cahalan M.D. 2017. T Cell Calcium Dynamics Visualized in a Ratiometric tdTomato-GCaMP6f Transgenic Reporter Mouse. Elife, Dec 14; 6:e27827.
Matheu M.P*., Othy S*., Greenberg M.L., Dong T.X., Schuijs M., Deswarte K., Hammad H., Lambrecht B.N., Parker I., and Cahalan M.D. 2015. Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat Commun Feb 5; 6:6219.
Othy, S., Topcu, S., Saha, C., Kothapalli, P., Lacroix-Desmazes, S., Kasermann, F., Miescher, S., Bayry, J., and Kaveri, S.V. 2014. Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin. Eur J Immunol. Jul; 44(7):2059-63.
Othy, S., Hegde, P., Topcu, S., Sharma, M., Maddur, M.S., Lacroix-Desmazes, S., Bayry, J., and Kaveri, S.V. 2013. IVIg inhibits encephalitogenic potential of pathogenic T cells and interferes with their trafficking to the central nervous system implicating ing sphingosine-1 phosphate receptor 1-mTOR axis. J Immunol May 1;190(9):4535-41.
Othy, S., Topcu, S., Kaveri, S., and Bayry, J. 2012. Effect of CC chemokine receptor 4 antagonism in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA Sep 11;109(37):E2412-3.
Othy, S., Bruneval, P., Topcu, S., Dugail, I., Delers, F., Lacroix-Desmazes, S., Bayry, J., and Kaveri, S. 2012. Effect of IVIg on human dendritic cell-mediated antigen uptake and presentation: role of lipid accumulation. J Autoimmun Sep;39(3):168-72.
Maddur, M.S., Othy, S., Hegde, P., Vani, J., Desmazes, SL., Bayry, J., and Kaveri, S.V. 2010. Immunomodulation by intravenous immunoglobulin: Role of regulatory T cells. J Clin Immunol May, 30, Suppl 1, S4-8.
NIH NIAID R01AI168063: Tissue-Specific Mechanisms of Regulatory T Cells in the CNS during Autoimmune Encephalomyelitis. PI: Shivashankar Othy.
NIH NIAID U01AI160397: Defining molecular mechanisms of combination adjuvants: a systems immunology, transcriptomics, and imaging approach”. PI: David Huw Davies; Role: Co-Investigator
Professional Societies
Society for Leukocyte Biology, USA.
American Association of Immunologists, USA.
Graduate Programs
Cell Biology
Cellular and Molecular Biosciences
Interdepartmental Neuroscience Program
Research Centers
Vaccine R & D Center
Institute for Immunology
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