Evidence of alloreactive T lymphocytes in fetal liver: implications for fetal hematopoietic stem cell transplantation

Abstract

Summary:The use of hematopoietic stem cells for in utero transplantation to create permanent hematochimerism represents a new concept in fetal therapy, although this approach has provided heterogeneous results. In this paper we have undertaken molecular, phenotypic and functional studies aimed at identifying the presence of fully competent T lymphocytes in samples of fetal livers and cord blood. We found mature VDJ TCR ␤ chain transcripts in fetal liver cells taken from 7 to 16 weeks of gestation and a similar pattern was detected in cord blood cells sampled from 13.5 to 20.5 weeks of gestation. A V␤8 gene sequence comparable to that detected in adult PBMC was found in fetal liver samples at 9 or 17 weeks gestation. PreT␣ message was detected in all samples and its expression decreased in fetal blood samples with increasing gestational age while C␣ message appeared at 9.4 weeks and its expression increased during gestational age. T cell clones obtained from fetal liver cells showed a mature TCR ␣␤ + , CD8 + phenotype and displayed strong alloreactivity against allo-MHC class I molecules. The presence of alloreactive T lymphocytes may explain the failure to engraft in fetuses older than 13 to 16 weeks and may provide insights into fetal liver transplantation. Bone Marrow Transplantation of gestation have been transplanted into fetuses at the 13th to 18th week of gestation. 6-8 Considerably better results have been obtained in fetuses affected by immunodeficiency syndromes such as SCID or Bare Lymphocyte diseases. 1,9 These findings raise the possibility that the fetus may develop an allogeneic immune reaction responsible for graft failure. Accordingly, fetal liver HSC were capable of engraftment in syngeneic, but not allogeneic recipient mice, 10 and successful allogeneic in utero transplantation of fetal HSC in sheep and monkeys occurred if both the donor and recipient fetuses were in a preimmune status. 5 Furthermore, we have recently reported 7 that in utero transplantation of an 18 week fetus with fetal HSC resulted in graft failure and after birth the recipient had a very high cytotoxic T cell precursor (CTLp) frequency against donor cells, thus indicating that generation of an alloimmune response rather than tolerance induction was the effect of the procedure.The development of T lymphocytes starts primarily in the embryonic thymus 11-13 after 8 weeks gestation, where they undergo a complex series of differentiation events leading to the expression of the T cell receptor (TCR) complex. 14 Efficient performance of this program appears to be dependent on cellular interactions between developing thymocytes and thymic stromal components. 15 These cells may then colonize the periphery, including the fetal liver itself, as the presence of phenotypically mature T cells has been demonstrated in 11-13 to 22 week old fetal livers. 16 Moreover, recent studies have shown that the liver is also a site for extrathymic T cell development and maturation. 17 Against this background, we have undertaken molecular, phenotypic ...

Ontogenic changes in CD95 expression on human leukocytes: prevalence of T-cells expressing activation markers and identification of CD95−CD45RO+ T-cells in the fetus

“…Nonetheless, the cellular immune system begins its development early in gestation around the end of the first trimester. Reports suggest that T cells can be found in liver and peripheral blood as early as 7 and 9 weeks' gestation, respectively, although their overall numbers are very low [1,2]. Intrathymic CD3…”

Immunoresponse against the transgene limits hematopoietic engraftment of mice transplanted in utero with virally transduced fetal liver

“…2,8 Moreover, T cells showing TCR rearrangement have been observed in human FL in the 13th week of gestation, 26 and FL NK cells and fetal T cells have been demonstrated alloreactive in vitro. [27][28][29] These lines of evidence could indicate the engraftment failure of FL hematopoietic cells transplanted in utero in allogeneic recipients.…”

Transplantation of a fetus with paternal Thy-1+CD34+cells for chronic granulomatous disease

“…These investigators further demonstrated that these fetal T cells were capable of alloreactivity. 43,44 Although the total number of T cells in the fetus around the time most IUT are performed is likely to be less than the number required to elicit an antigen-specific response, a far greater frequency of T cells react against allogeneic MHC. T cells emerging from the thymus in the weeks following IUT may also react against donor cells if thymic colonization by the donor cells does not occur rapidly.…”