Research Article: Defining Immune Engagement Thresholds for In Vivo Control of Virus-Driven Lymphoproliferation

Date Published: June 26, 2014

Publisher: Public Library of Science

Author(s): Cristina Godinho-Silva, Sofia Marques, Diana Fontinha, Henrique Veiga-Fernandes, Philip G. Stevenson, J. Pedro Simas, Edward Usherwood.


Persistent infections are subject to constant surveillance by CD8+ cytotoxic T cells (CTL). Their control should therefore depend on MHC class I-restricted epitope presentation. Many epitopes are described for γ-herpesviruses and form a basis for prospective immunotherapies and vaccines. However the quantitative requirements of in vivo immune control for epitope presentation and recognition remain poorly defined. We used Murid Herpesvirus-4 (MuHV-4) to determine for a latently expressed viral epitope how MHC class-I binding and CTL functional avidity impact on host colonization. Tracking MuHV-4 recombinants that differed only in epitope presentation, we found little latitude for sub-optimal MHC class I binding before immune control failed. By contrast, control remained effective across a wide range of T cell functional avidities. Thus, we could define critical engagement thresholds for the in vivo immune control of virus-driven B cell proliferation.

Partial Text

The gamma-herpesviruses (γHVs) infect >90% of humans and cause diseases including nasopharyngeal carcinoma, African Burkitt’s lymphoma and Kaposi’s Sarcoma. Their colonization of circulating memory B cells is crucial to persistence and hence to disease ontogeny. Viral latency gene expression in B cells provides an immune target [1] that has been exploited to prevent lymphoproliferative disease in acutely immunodeficient patients by T cell transfer [2]. However, extending this approach to established cancers and developing related vaccines have proved difficult. A significant problem is that the narrow species tropisms of human γHVs severely restrict in vivo analysis, and hence an understanding of how empirical therapies such as adoptive T cell transfer work.

Gamma-herpesvirus epitope recognition by CTL has been studied extensively [1], [54], but ours is the first quantitative assessment of how epitope/MHC class I/TcR complex formation affects host colonization. Where no latency epitope expression existed, introducing one led to a profound, CTL-dependent suppression of virus-driven lymphoproliferation. This was consistent with the impact of endogenous epitope presentation in H2d mice [29]. The latter affected only long-term viral loads; OVA expression in H2b mice also conferred susceptibility to CTL during acute lymphoproliferation, when trans-acting immune evasion operates [1]. This greater effect of epitope presentation possibly reflected differences in host susceptibility to immune evasion: the MuHV-4 K3 degrades H2Kb relatively poorly [19] and degrades TAP better in H2d than H2b cells [20].




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