Immune engagement thresholds for CD8+ T CELL control of yherpesvirus-driven B CELL

Tese de doutoramento, Ciências Biomédicas (Ciências Biopatológicas), Universidade de Lisboa, Faculdade de Medicina, 2014

Gamma-herpesviruses (γHVs) are oncogenic pathogens that drive the proliferation of latently infected cells in germinal centres to achieve long-term persistence in memory B cells in face of host competent immune responses. Persistence relies on a dynamic balance between virusdriven B cell proliferation and control by CD8+ cytotoxic T lymphocytes (CTLs). If this virus-host equilibrium is disrupted, as is the case when CD8+ CTL function is compromised, latently infected B cells can proliferate unchecked leading to the development of lymphoproliferative diseases. Viral latency epitopes presented in infected cells have been successfully exploited to prevent or treat γHV-associated lymphoproliferative disorders by adoptive CTL transfer in the transplantation setting. However, extending this approach to other γHV-associated tumours and to the development of prophylactic and therapeutic vaccines remains challenging. The narrow species tropism of human γHVs severely restricts in vivo analysis. Hence, an important unknown is how in vitro CD8+ CTL killing correlates with effective in vivo immune protection. The aim of this thesis was to identify immune engagement thresholds for effective in vivo CD8+ CTL control of virus-driven B cell proliferation. Infection of laboratory mouse with murid herpesvirus-4 (MuHV-4) was used as an experimental model to investigate, for a single latently expressed epitope, how MHC class I binding and CD8+ T cell functional avidity impact on infection control. The ability of MuHV-4 recombinants that differed only in latency epitope presentation to elicit epitope-specific CD8+ CTL responses and to drive the proliferation of latently infected B cells was assessed. CD8+ CTL control of latency amplification in GC B cells was critically dependent on strong epitope binding to MHC class I. By contrast, CD8+ T cell recognition was effective over a broad range of functional avidities before control of virus-driven lymphoproliferation failed, thus showing relatively good tolerance for sub-optimal T cell receptor engagement. In summary, this study identified critical MHC class I and CD8+ T cell engagement thresholds for in vivo CD8+ CTL control of virus-driven B cell proliferation. Defining in vivo thresholds of immune engagement for the effective control of γHV persistent infection is fundamental for the development of successful immunotherapies and vaccines.

Fundação para a Ciência e a Tecnologia (FCT)