Uttenthal, BJ; (2012) T cell receptor-transduced regulatory T cells: functional studies in models of graft-versus-host disease. Doctoral thesis , UCL (University College London).

Abstract

Alloreactive immune responses directed against malignant cells in recipients of allogeneic haematopoietic stem cell transplants are able to cure patients with haematological cancers. However, such immune responses may cause severe morbidity when directed against healthy recipient tissue, resulting in graft-versus-host disease (GvHD). Naturally occurring regulatory T cells (Tregs) are CD4+ T cells characterized by their expression of the transcription factor Foxp3. Whilst adoptively transferred polyclonal Tregs suppress GvHD in several murine models, their lack of specificity may compromise beneficial immunity against malignancy or infection. The generation of MHC class I-restricted, alloantigen-specific Tregs would allow them to recognize antigen presented directly on GvHD target tissues, concentrating their sites of activation at these tissues and potentially reducing non-specific immune suppression. I have generated ‘converted’ Tregs through retroviral transfer of genes encoding Foxp3 and specific MHC class I-restricted T cell receptors (TCRs) into conventional CD4+ T cells. I used the 2C-TCR, which recognizes the MHC class I molecule H-2Ld, expressed in Balb/c and other H-2d mice, in complex with the ubiquitously expressed peptide p2Ca; and the MH TCR, which recognizes the MHC class I molecule H-2Db, expressed in B6 and other H-2b mice, in complex with the male peptide WMHHNMDLI. In vitro, Foxp3 2C-TCR-transduced B6 CD4+ T cells are hyporesponsive to stimulation and are able to suppress the alloreactive proliferative response of B6 CD4+ and CD8+ T cells to Balb/c splenocytes, consistent with the acquisition of regulatory function. When adoptively transferred to lethally irradiated Balb/c recipients of MHC-mismatched B6 bone marrow and conventional T cells, Foxp3 2C-TCR-transduced B6 CD4+ T cells reduce early proliferation of donor T cells, weight loss and GvHD score in the recipients. Similarly, CD4+ T cells transduced with Foxp3 and the MH-TCR are able to suppress allogeneic responses both in vitro and in vivo. However, while both the 2C-TCR and the MH TCR confer specificity to their cognate antigens in vitro, antigen specificity of suppression is not evident in these in vivo models. In this thesis I show that the endogenous TCR of transduced CD4+ T cells contributes to this lack of specificity, a finding that has important implications for the use of class I-restricted TCRs alongside Foxp3 in CD4+ T cells to direct regulatory activity.

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