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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.

Background: As initiators of immune responses, dendritic cells (DCs) are required for antigen (Ag)‐specific activation of naïve T cells in the defense against infectious agents. The increased susceptibility to and severity of infection seen in chronic alcoholics could be because of impaired DCs initiation of naïve T‐cell responses. Specifically, these DCs may not provide adequate Signals 1 (Ag presentation), 2 (costimulation), or 3 (cytokine production) to these T cells.

Chronic ethanol consumption results in immunodeficiency. Previous work with chronic ethanol‐fed mice has shown reduced splenic weight and cellularity, including reduced numbers of CD8+T cells. However, antigen‐specific CD8+and CD4+T cell responses in chronic ethanol‐fed mice have been studied relatively little. We have used an attenuated Listeria monocytogenesstrain DPL 1942 (LM ΔactA) to inoculate mice and subsequently used CD4+and CD8+immunodominant peptides of LM to measure the CD4+and CD8+T cell responses after chronic ethanol exposure. We found no major differences between control and ethanol‐fed mice in the kinetics and persistence of antigen‐specific CD4+T cells in response to an immunodominant LM peptide, as measured by intracellular IFN‐γ staining. In contrast to CD4+responses, three methods of in vitro antigen presentation indicated that the primary response of CD8+T cells to several different epitopes was reduced significantly in mice chronically fed ethanol. Antigen‐specific CD8+T cells were also reduced in chronic ethanol‐fed mice during the contraction phase of the primary response, and memory cells evaluated at 29 and 60 days after inoculation were reduced significantly. BrdU proliferation assays showed that in vivo proliferation of CD8+T cells was reduced in ethanol‐fed mice, and IL‐2‐dependent in vitro proliferation of naive CD8+T cells was also reduced. In conclusion, these results suggest that antigen‐specific CD4+T cell responses to LM are affected little by chronic ethanol consumption; however, antigen‐specific CD8+T cell responses are reduced significantly, as are in vivo and in vitro proliferation. The reduction of antigen‐specific CD8+T cells may contribute strongly to the immunodeficiency caused by ethanol abuse.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Prenatal transplantation capitalizes on the unique fetal environment, allowing for life-long engraftment of allogeneic stem cells without the need for harsh conditioning regimens. A prerequisite for stable engraftment of allogeneic cells likely requires the negative selection of donor-specific host effector T cells (Teff) and the support of donor-specific regulatory T cells (Tregs). However, little is known about the interplay between these cell types during development. The purpose of this study was to characterize the dynamic relationship between donor-specific Teffand Tregsas they emerge during development.

Invariant NKT (iNKT) cells are glycolipid-reactive alpha/beta T cells which have an important role in the regulation of GVHD after allogeneic bone marrow transplantation. During thymic development, murine iNKT cells divide into three transcriptionally distinct lineages-NKT1, NKT2, and NKT17 that differ in their cytokine expression profile both at rest and upon antigen recognition via their TCR. Given that the lineage profile of iNKT cells varies dramatically between inbred strains of mice, it has been postulated that recognition of allospecific glycolipids determines iNKT cell lineage-fate decisions. Therefore, we challenged this hypothesis in a murine model of prenatal allogeneic transplantation to determine if the lineage commitment of immature iNKT cells was intrinsically programmed or extrinsically regulated by the allospecific environment during development.

Invariant NKT (iNKT) cells have been shown to be pro-inflammatory or anti-inflammatory in many pathologic conditions including infections, cancer, autoimmune diseases and allergy. Additionally, early expansion of iNKT cells correlates with successful engraftment and low incidence of graft-versus host disease suggesting a role for iNKT cells in tolerance to allogeneic transplantation. iNKT cells recognize glycolipids bound to CD1d via their T cell receptor (TCR), but also express the inhibitory receptors for MHC class I ligands (MHC I.) Little is known regarding the importance of iNKT cell self-recognition of MHC I during development and the occurrence of autoimmunity, allergy or tolerance to in utero hematopoietic cellular transplantation (IUHCT). Given the importance of NK cell self-recognition during development, we hypothesized that, like NK cells, self-engagement of MHC I inhibitory receptors during development alters the phenotype and function of self-responsive iNKT cells.

No relevant conflicts of interest to declare.