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

Abstract

The primary benefits of in utero hematopoietic cellular transplantation (IUHCT) arise from transplanting curative cells prior to the immunologic maturation of the fetus. However, this approach has been routinely successful only in the treatment of congenital immunodeficiency diseases that include an inherent NK cell deficiency despite the existence of normal maternal immunity in either setting. These observations raise the possibility that fetal NK cells function as an early barrier to allogeneic IUHCT. Herein, we summarize the findings of previous studies of prenatal NK cell allospecific tolerance in mice and in humans. Cumulatively, this new information reveals the complexity of the fetal immune response in the setting of rejection or tolerance and illustrates the role for fetal NK cells in the final endorsement of allospecific prenatal tolerance.

Maternal and Fetal Immune Response to In Utero Stem Cell Transplantation

“…This is most evident with the observation that engraftment or rejection may occur in alternating littermates exposed to the same maternal influence (10, 11). The rejection may occur within the first few weeks after birth or may follow months of decay in the chimerism level whereas parallel transplantation in a naturally tolerant congenic strain combination revealed remarkably stable engraftment in nearly all recipients even at the lowest chimerism levels Furthermore, rejection in the allogenic recipients was complete with no detectable chimerism and normalization of the alterations in host lymphocyte populations that are typically seen even in the setting of microchimerism In our laboratory, this pattern was found to be independent of a potential maternal immune response as the rate of rejection was unaffected by the use of naïve foster dams and no maternal cells have been detected anywhere within the recipient mice after birth(11, 28, 29). A detailed assessment of the transplanted offspring revealed that engraftment or rejection in littermates correlated with a level of initial chimerism greater than or less than 1.8% of circulating cells (chimerism threshold).…”

“…The identification of the chimerism threshold as a reliable predictor of engraftment suggested that NK cell education was essential to durable NK cell tolerance. Subsequent experiments led to the characterization of a sophisticated process for prenatal NK cell allospecific education akin to thymic T-cell selection that resulted in the elimination of alloreactive (hostile) phenotypes from the mature pool of NK cells in stable chimeras (28, 29). In this process, NK cells that expressed allospecific activating Ly49 receptors without co-expression any of the allospecific Ly49 inhibitory receptors were deleted or rendered functionally anergic.…”

Tolerance to noninherited maternal antigens, reproductive microchimerism and regulatory T cell memory: 60 years after ‘Evidence for actively acquired tolerance to Rh antigens’

“…The study of in utero transplantation of genetically foreign cells also exploits the tolerogenic properties unique to fetal development and provides important mechanistic clues on NIMA-specific tolerance. 40-42 The theoretical advantage of in utero transplantation is that therapeutic introduction of genetically foreign cells into the fetal recipient prior to maturation of adaptive immune components can induce long-term donor-specific tolerance without the need for toxic myeloablative conditioning. Animal models of in utero haematopoietic cell transplantation highlight the critical importance of a minimum threshold of antigen exposure necessary to establish and maintain allo-specific tolerance.…”

“…Animal models of in utero haematopoietic cell transplantation highlight the critical importance of a minimum threshold of antigen exposure necessary to establish and maintain allo-specific tolerance. 40,43-48 Therefore, tolerance to NIMA that parallels persistence of maternal origin microchimeric cells also likely hinges on a minimum level of exposure to microchimeric maternal cells. 17,44 Further study is needed however, to determine how the level of maternal microchimerism may dictate alternate outcomes of autoimmunity or NIMA-specific tolerance.…”

Prenatal Allogeneic Tolerance in Mice Remains Stable Despite Potent Viral Immune Activation

“…Conversely, the in vivo elimination of host NK cells abrogates the graft rejection seen below the chimerism threshold and preserves long-term engraftment. In this way, NK cells function as a secondary barrier to prenatal engraftment and explain the clinical pattern of enhanced success in NK cell-deficient recipients of IUHCT (18–21). …”