Conserved mechanisms underlying loss of tolerance to allogeneic tissues in Botryllus schlosseri chimeras and HSC transplantation

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 34 B. schlosseri cell populations, identified hematopoietic stem cell (HSC), progenitors, immune-effector cells, and the HSC niche. Completing a full model for HSC transplantation. 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 pro-inflammatory 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. PNAS, 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.