Experimental support for the ecoimmunity theory: Distinct phenotypes of nonlymphocytic cells in SCID and wild-type mice

David E. Ochayon, Boris M. Baranovski, Peter Malkin, Ronen Schuster, Noa Kalay, Rotem Ben-Hamo, Ido Sloma, Justin Levinson, Jared Brazg, Sol Efroni, Eli C. Lewis, Uri Nevo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Immune tolerance toward “self” is critical in multiple immune disorders. While there are several mechanisms to describe the involvement of immune cells in the process, the role of peripheral tissue cells in that context is not yet clear. The theory of ecoimmunity postulates that interactions between immune and tissue cells represent a predator–prey relationship. A lifelong interaction, shaped mainly during early ontogeny, leads to selection of nonimmune cell phenotypes. Normally, therefore, nonimmune cells that evolve alongside an intact immune system would be phenotypically capable of evading immune responses, and cells whose phenotype falls short of satisfying this steady state would expire under hostile immune responses. This view was supported until recently by experimental evidence showing an inferior endurance of severe combined immunodeficiency (SCID)-derived pancreatic islets when engrafted into syngeneic immune-intact wild-type (WT) mice, relative to islets from WT. Here we extend the experimental exploration of ecoimmunity by searching for the presence of the phenotypic changes suggested by the theory. Immune-related phenotypes of islets, spleen, and bone marrow immune cells were determined, as well as SCID and WT nonlymphocytic cells. Islet submass grafting was performed to depict syngeneic graft functionality. Islet cultures were examined under both resting and inflamed conditions for expression of CD40 and major histocompatibility complex (MHC) class I/II and release of interleukin-1a (IL-1a), IL-1b, IL-6, tumor necrosis factor-a (TNF-a), IL-10, and insulin. Results depict multiple pathways that appear to be related to the sculpting of nonimmune cells by immune cells; 59 SCID islet genes displayed relative expression changes compared with WT islets. SCID cells expressed lower tolerability to inflammation and higher levels of immune-related molecules, including MHC class I. Accordingly, islets exhibited a marked increase in insulin release upon immunocyte depletion, in effect resuming endocrine function that was otherwise suppressed by resident immunocytes. This work provides further support of the ecoimmunity theory and encourages subsequent studies to identify its role in the emergence and treatment of autoimmune pathologies, transplant rejection, and cancer.

Original languageEnglish
Pages (from-to)1575-1588
Number of pages14
JournalCell Transplantation
Issue number8
StatePublished - 2016

Bibliographical note

Publisher Copyright:
© 2016 Cognizant, LLC.


  • Autoimmunity
  • Ecoimmunity
  • Lymphocytes
  • Major histocompatibility complex (MHC) class I
  • Pancreatic islets


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