Research
Human cytomegalovirus (HCMV) provides a paradigm for how a complex viral pathogen persists and evades immune responses. Our programme of research seeks to addressed a number of important questions concerning the immunobiology of HCMV. With a particular focus on the generation, maintenance and function of memory CD8+ T cells and the immune evasion mechanism employed by the virus to modulate Natural Killer cell function.
Our longitudinal study of primary HCMV infection has shown that T cell receptor affinity appears crucial for the selection of T cells into long-term memory from the initial highly polyclonal T cell response. This process is not stochastic, as in many murine models, and is remarkably rapid, occurring over weeks not years. Selected T cell clones are very long lived – possibly retained for life.
The CD8+ T cell response to HCMV is often dominated by a distinctive population of revertant memory T cells (CD45RA+ CD28- CD8+) which were thought to have a low replicative capacity and to be close to terminal differentiation. However, we have shown these cells utilise an alternative pathway of co-stimulation to classically defined memory T cells, via the 41BB-41BBL interaction, enabling them to proliferate and re-express important chemokine receptors and adhesion molecules which allow re-homing to lymph nodes and peripheral tissues. The high frequency of these HCMV-specific revertant memory T cells maintained in virus carriers suggests they are crucial for immune control.
HCMV evades cytotoxic T cells by down-regulating class I MHC, but then has to evade natural killer (NK) cells. We have recently described a novel MHC-like gene (UL142) unique to clinical isolates that inhibits NK cell lysis in a clonally dependant manor. We are currently defining the mechanism of action of the novel viral NK evasion gene product (UL142) by identifying its ligand and how this mediates evasion of NK cell cytotoxicity.
Publications
Mason GM, Jackson S, Okecha G, Poole E, Sissons JG, Sinclair J, Wills MR. Human cytomegalovirus latency-associated proteins elicit immune-suppressive IL-10 producing CD4⁺ T cells. PLoS Pathog. 2013;9(10):e1003635.
Cano F, Bye H, Duncan LM, Buchet-Poyau K, Billaud M, Wills MR, Lehner PJ. The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with MHC-I mRNA degradation. EMBO J. 2012 Aug 29;31(17):3596-606.
Human cytomegalovirus latency alters the cellular secretome, inducing cluster of differentiation (CD)4+ T-cell migration and suppression of effector function. Mason GM, Poole E, Sissons JG, Wills MR, Sinclair JH. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14538-43.
- Huang MM, Kew VG, Jestice K, Wills MR, Reeves MB.
Efficient human cytomegalovirus reactivation is maturation dependent in the Langerhans dendritic cell lineage and can be studied using a CD14+ experimental latency model.J Virol. 2012 Aug;86(16):8507-15.
Jackson SE, Mason GM, Wills MR. Human cytomegalovirus immunity and immune evasion. Virus Res. 2011 May;157(2):151-60.
Bennett NJ, Ashiru O, Morgan FJ, Pang Y, Okecha G, Eagle RA, Trowsdale J, Sissons JG, Wills MR. Intracellular sequestration of the NKG2D ligand ULBP3 by human cytomegalovirus. J Immunol. 2010 Jul 15;185(2):1093-102.
