Hiwarkar, Prashant Ramdas; (2018) Characterization of CD4+ T-cell expansion after cord blood transplantation and its role in anti-leukaemic effects. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In the absence of serotherapy, cord blood transplantation (CBT) is followed by a rapid and unique CD4+ biased immune reconstitution derived from T cells within the graft. The mechanism for this enhanced CD4+ biased reconstitution which differs from that of other stem cell sources and correlates with rapid anti-viral and enhanced graft-versus-leukaemia responses is not known. Lymphopoiesis following stem cell transplantation may be derived from foetal or adult haematopoietic stem cells. We therefore sought to determine whether recapitulation of foetal lymphopoiesis mediates rapid expansion of cord blood CD4+ T cells into the lymphopenic environment created by transplant conditioning. We compared the foetal CD4+ T-cell transcriptome with the transcription profile of naïve CD4+ T cells from normal donor cord blood (n=9), normal donor peripheral blood (n=9), and reconstituting naïve CD4+ T cells following CBT (n=3) and bone marrow transplant (BMT) (n=3). Our findings confirm that cord blood CD4+ T cells and CD4+ T cells reconstituting after CBT retain the properties of foetal ontogenesis and can rapidly restore the CD4+ T-cell biased adaptive immunity through enhanced T-cell receptor (TCR) signalling. TCR sensitivity dictates the ability of T cells to respond to self-peptide and foreign antigens, and the emerging data suggests that unrelated CBT, particularly in the context of HLA-mismatching and a T-cell replete graft, may reduce leukaemic relapse. Therefore, I aimed to study the role of foetal-derived adaptive immune system following T-cell replete CBT in mediating graft-versus-tumour responses and dissect the underlying cellular mechanisms. To do this, the ability of HLA-mismatched cord blood and adult peripheral blood T cells to eliminate Epstein-Barr virus (EBV)-driven human B-cell lymphoma was compared, in a xenogeneic NOD/SCID/IL2rgnull mouse model. In our model, cord blood T cells mediated enhanced anti-tumour effects by rapid infiltration of the tumour with CCR7+ CD8+ T cells, and prompt induction of cytotoxic CD8+ and Th1 CD4+ T cells in the tumour microenvironment. Conversely, in the peripheral blood group, this anti-lymphoma effect was impaired because of delayed tumoural infiltration of peripheral blood T cells, and a relative bias toward suppressive Th2 and T regulatory cells. Our data suggest that, despite being naturally programmed toward tolerance, reconstituting T cells after unrelated T-cell replete CBT may provide superior Tc1-Th1 anti-tumour effects against high-risk haematological malignancies.

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