Tolerance and MHC-restriction following thymus transplantation

Supervisors: Professor Tessa Crompton and Dr Anna Furmanski

Aim: The purpose of this project is to test the hypothesis that T-cells are restricted by host MHC following non-MHC-matched thymus transplantation, as a result of formation of chimeric thymus, but that tolerance to self (host) is incomplete.

Complete DiGeorge Syndrome (DGS), a rare, fatal congenital athymia, can be treated by unmatched thymus transplantation, which reconstitutes naïve T-cell output, although not to normal levels[1]. Autoimmunity has been observed in one-third of thymus transplant recipients[1,2], presumably due to MHC -mismatching. We used the athymic nude mouse[3,4] as a recipient for human thymus grafts, to establish a model of thymus transplantation for studying tolerance induction and autoimmunity[5]. These xenografts supported mouse T-cell development, and no human T-cells were produced. Surprisingly, we did not detect multi-organ autoimmune disease. However, all transplanted mice developed striking depigmentation and loss of hair follicles. Transfer of T-cells from transplanted nudes to syngen eic black-coated furry Rag-/-recipients caused progressive, persistent coat-hair whitening, which preceded patchy hair-loss in depigmented areas. These phenomena could be induced by transfer of sorted CD4+ T-cells alone.

Immunofluorescent analysis suggested that Trp2+ melanocyte-lineage cells were decreased in depigmented hair follicles, and pathogenic T-cells upregulated activation markers when exposed to C57BL/6 melanocytes in vitro, suggesting that these T-cells are not tolerant to self-melanocyte antigens.

In this project we will use and develop our model of thymus transplantation into athymic nude mice to investigate the mechanisms of tolerance induction and positive selection of thymocytes in the transplanted tissue, and the MHC-requirements for peripheral T-cell homeostasis function, and response to vaccines. We will use cell transfer into mice of different MHC to test MHC -restriction and alloreactivity, and we will investigate the cellular composition of the transplanted thymus tissue, and requirements for tolerance to skin antigens. In addition we will use a mouse-into-mouse model to investigate TCR repertoire selection.

References:
1) Markert ML et al. Blood. 2007;109:4539-4547.
2) Levy E et al. Annales de dermatologie et de venereologie. 2012;139:468-471.
3) Pantelouris EM. Nature. 1968;217:370-371.
4) Nehls M et al. Nature. 1994;372:103-107.
5) Furmanski AL et al. J Invest Dermatol. 2013, in press.