CONSERVED MECHANISMS UNDERLYING LOSS OF TOLERANCE TO ALLOGENEIC TISSUES IN BOTRYLLUS SCHLOSSERI CHIMERAS
Benyamin Rosental, Ben Gurion University of the Negev, Israel
Benyamin Rosental1,2*, Mark Kowarsky3*, Jun Seita2,4, Daniel M. Corey2, Katherine J. Ishizuka2, Karla J. Palmeri2, Shih-Yu Chen5, Rahul Sinha2, Jennifer Okamoto6, Gary Mantalas7, Lucia Manni8, Tal Raveh2, D. Nathaniel Clarke2, Aaron M. Newman2, Norma F. Neff6, Garry P. Nolan5, Stephen R. Quake6,7,&, Irving L. Weissman2,6& and Ayelet Voskoboynik2,6&.
1 French Associates Institute for Agriculture and Biotechnology of Drylands, the Jacob Blaustein Institutes for Desert Research, Ben Gurion University of the Negev, Israel.
2Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center, and Hopkins Marine Station, Stanford University, CA, USA.
3Department of Physics, Stanford University, CA, USA.
4AI based Healthcare and Medical Data Analysis Standardization Unit, Medical Sciences Innovation Hub Program, RIKEN, Japan.
5Department of Microbiology and Immunology, Stanford University School of Medicine, USA.
6Chan Zuckerberg Biohub, San Francisco CA, USA.
7Departments of Applied Physics and Bioengineering, Stanford University, CA, USA
8Dipartimento di Biologia, Università degli Studi di Padova, Italy. *,& Equal contribution.
The mechanisms that sustain immunological non-reactivity are the basis for understanding the maintenance of tissue in syngeneic and allogeneic settings. While most transplantation rejection occurs due to the adaptive immune response, the pro-inflammatory response of innate immunity is necessary for the activation of adaptive immunity – both in syngeneic and allogeneic settings. We study a unique chordate model, Botryllus schlosseri, that lacks a classic adaptive immune system, yet has the ability to reject allogeneic individuals or form chimeras with compatible animals. This organism demonstrates three major innate immunity responses: non-inflammatory program cell removal, acute rejection (between non-compatible animals) and allogeneic resorption (between compatible colonies that formed chimeras). Using flow cytometry, whole-transcriptome sequencing of defined cell populations and tissues, and diverse functional assays, we isolated 24 endpoint B. schlosseri cell populations, identified hematopoietic stem cell (HSC), progenitors, immuneeffector cells, and the HSC niche. Furthermore, we identified a B. schlosseri cytotoxic cell population originating from large granular lymphocyte-like cells and demonstrated their function in acute and chronic rejection processes. Studying the molecular and cellular framework underlying loss of tolerance to allogeneic tissues within the B. schlosseri chimera, we found that developmental cell death programs license cytotoxic cells to eliminate histocompatible partners. This study demonstrates that interactions between proinflammatory and damaged tissue removal, lead to robust cytotoxic and phagocytic clearance programs within the allogeneic microenvironment.
References: Corey DM*, Rosental B*, Kowarsky M, Sinha R, Ishizuka KJ, Palmeri KJ, Quake SR, Voskoboynik A, Weissman IL. Developmental cell death programs license cytotoxic cells to eliminate histocompatible partners. Proc Natl Acad Sci U S A, 2016.
Rosental B, Kowarsky M, Seita J, Corey DM, Ishizuka KJ, Palmeri KJ, Chen SY, Sinha R, Okamoto J, Mantalas G, Manni L, Raveh T, Clarke DN, Tsai JM, Newman AM, Neff NF, Nolan GP, Quake SR, Weissman IL, Voskoboynik A. Complex mammalian-like haematopoietic system found in a colonial chordate. Nature, 2018.