De Ascensão Santos e Sousa, Pedro Miguel; (2017) A systems immunology approach to graft-versus-host disease. Doctoral thesis , UCL (University College London).

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Abstract

It is not known why only certain tissues are prone to graft-versus-host disease (GVHD) injury following allogeneic hematopoietic stem cell transplantation despite widespread antigen expression. Although it is known that T cell effector pathways can have distinct effects upon individual GVHD organs, there has been no unbiased or systems-wide approach to defining the mechanisms underlying tissue-specific pathology. This thesis reports the results from a systems immunology approach to address the hypothesis that GVHD target tissues exert dominant, idiosyncratic roles in regulating effector T cell functions. To test this concept, gene expression profiles of effector CD8+ T cells infiltrating lymphoid and GVHD target organs were compared in two clinically relevant murine GVHD models. Using Weighted Gene Network Correlation Analysis, a dichotomy between the transcriptomes of T cells in peripheral tissues and lymphoid organs was identified. These profiles diverged sharply between the different GVHD target organs, and between individual sub-compartments of single organs, independently of the TCR repertoire and antigen distribution. In the skin, expression of a broad effector program was determined by the transition of T cells from the dermis to the epidermis, in a process regulated by Langerhans cells (LC). In the absence of LC, T cells were rendered incapable of up-regulating the full panoply of effector genes, showed impaired differentiation into resident memory cells and failed to induce cutaneous GVHD. By performing localized LC depletion, it was demonstrated that LC regulated T cell effector programs in situ within the epidermis by providing signals to enhance local cytokine production, promote resistance to apoptosis and enhance local survival. Collectively, these data demonstrate that GVHD is defined by tissue-autonomous regulation of effector T cells; in the skin, this is dictated by interaction with epidermal LC in situ. This work provides a rationale for precision therapies directed at blocking GVHD in individual tissues.

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