Transplantation Tolerance to a Single Noninherited MHC Class I Maternal Alloantigen Studied in a TCR-Transgenic Mouse Model

Abstract

The mechanisms underlying tolerance to noninherited maternal Ags (NIMA) are not fully understood. In this study, we designed a double-transgenic model in which all the offspring’s CD8+ T cells corresponded to a single clone recognizing the Kb MHC class I protein. In contrast, the mother and the father of the offspring differed by the expression of a single Ag, Kb, that served as NIMA. We investigated the influence of NIMA exposure on the offspring thymic T cell selection during ontogeny and on its peripheral T cell response during adulthood. We observed that anti-Kb thymocytes were exposed to NIMA and became activated during fetal life but were not deleted. Strikingly, adult mice exposed to NIMA accepted permanently Kb+ heart allografts despite the presence of normal levels of anti-Kb TCR transgenic T cells. Transplant tolerance was associated with a lack of a proinflammatory alloreactive T cell response and an activation/expansion of T cells producing IL-4 and IL-10. In addition, we observed that tolerance to NIMA Kb was abrogated via depletion of CD4+ but not CD8+ T cells and could be transferred to naive nonexposed mice via adoptive transfer of CD4+CD25high T cell expressing Foxp3 isolated from NIMA mice.