Transplantation tolerance to a single noninherited MHC class I maternal alloantigen studied in a TCR-transgenic mouse model

J Immunol. 2011 Feb 1;186(3):1442-9. doi: 10.4049/jimmunol.1003023. Epub 2010 Dec 22.

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 K(b) MHC class I protein. In contrast, the mother and the father of the offspring differed by the expression of a single Ag, K(b), 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-K(b) thymocytes were exposed to NIMA and became activated during fetal life but were not deleted. Strikingly, adult mice exposed to NIMA accepted permanently K(b+) heart allografts despite the presence of normal levels of anti-K(b) 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 K(b) was abrogated via depletion of CD4(+) but not CD8(+) T cells and could be transferred to naive nonexposed mice via adoptive transfer of CD4(+)CD25(high) T cell expressing Foxp3 isolated from NIMA mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / genetics
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Female
  • Graft Survival / genetics
  • Graft Survival / immunology
  • H-2 Antigens / biosynthesis
  • H-2 Antigens / genetics*
  • H-2 Antigens / immunology*
  • Heart Transplantation / immunology
  • Lymphocyte Depletion
  • Male
  • Maternal-Fetal Exchange / genetics
  • Maternal-Fetal Exchange / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Models, Immunological
  • Pregnancy
  • Receptors, Antigen, T-Cell / biosynthesis
  • Receptors, Antigen, T-Cell / genetics*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Thymus Gland / metabolism
  • Transplantation Tolerance / genetics*

Substances

  • H-2 Antigens
  • H-2Kb protein, mouse
  • Receptors, Antigen, T-Cell