Trogocytosis as a mechanistic link between chimerism and prenatal tolerance

Abstract

In utero hematopoietic cellular transplantation (IUHCT) holds great promise for the treatment of congenital diseases of cellular dysfunction such as sickle cell disease, immunodeficiency disorders and inherited metabolic disorders. However, repeated failures in clinical cases of IUHCT that do not involve an immunodeficiency disease force a closer examination of the fetal immune system. While the mechanisms regulating T cell tolerance have been previously studied, the educational mechanisms leading to NK cell tolerance in prenatal chimeras remain unknown. As a low level of donor cells (1.8%) is required to induce and maintain this tolerance, it is likely that these mechanisms employ indirect host-donor interaction. This report examines donor-to-host MHC transfer (trogocytosis) as an intrinsic mechanism regulating the development and maintenance of NK cell tolerance in prenatal chimeras. The findings demonstrate that phenotypically tolerant host NK cells express low levels of transferred donor MHC antigens during development and later as mature cytotoxic lymphocytes. Further study is needed to understand how the cis-recognition of transferred donor MHC ligand influences the selection and maintenance of tolerant NK cells in prenatal chimeras.

NK cell tolerance as the final endorsement of prenatal tolerance after in utero hematopoietic cellular transplantation

“…The studies by Kim et al (1998 , 1999 ) first demonstrated that allospecific T cell tolerance can be reliably achieved by IUHCT to the murine fetus at E14 resulting in the deletion and anergy of donor-reactive T cells. Subsequent studies confirmed the allo-receptivity of C57BL/6 and Balb/c fetuses at E14 ( Shaaban et al, 1999 , 2006 ; Hayashi et al, 2002 ; Durkin et al, 2008a , b ; Alhajjat et al, 2013 ; Nijagal et al, 2013 ). Collectively, these findings suggest that the potential for donor-specific tolerance to reliably develop following IUHCT is lost shortly after the appearance of mature single positive T cells.…”

“…Improved competition for available host niches would logically lead to higher levels of early chimerism. Previous reports from our group illustrate that the early chimerism level (discussed below) is the major determinant of successful allogeneic engraftment and link this to the development of donor-specific NK cell tolerance ( Shaaban et al, 2006 ; Durkin et al, 2008a , b ; Alhajjat et al, 2013 ). However, a competitive-niche model struggles to explain the dichotomous observations for immunodeficient vs. non-immunodeficient cases and seems to disregard the obvious difference.…”

Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Allorecognition through the Activating Receptor during Development

“…In those experiments, host NK cells from chimeric mice naturally expressed both activating and inhibitory Ly49 receptors that were specific for the donor MHC class I ligands. Following “pre-immune” transplantation to an otherwise un-manipulated allogeneic fetal host, direct trans- recognition of donor cells by activating and inhibitory receptors likely played a dominant role in the education of host NK cells although indirect or even cis recognition by inhibitory receptors resulting from MHC transfer may have had an important role in the education of host NK cells (17–20). It may be speculated that a threshold level of circulating chimerism was critical to each of these mechanisms.…”

Maternal and Fetal Immune Response to In Utero Stem Cell Transplantation

“…Here, NK cell education hinged on allorecognition by the activating receptor and subsequent upregulation of the inhibitory receptors in a developmentally-limited window (29). These changes were proven to be remarkably stable in mature chimeras even in the face of a potent viral infection (31) and were supported by adjunct mechanisms such as MHC transfer (trogocytosis) that provided sustained cisrecognition of donor ligand in the absence of trans- interaction (32). The essence of this quantitative model for NK cell education is that a minimal amount of donor chimerism is required for induction and maintenance of NK cell tolerance thereby establishing a theoretical explanation for many of the observations of clinical IUHCT.…”