Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells

Cytomegaloviruses (CMVs) are host species-specific in their replication. It is a hallmark of all CMVs that productive primary infection is controlled by concerted innate and adaptive immune responses in the immunocompetent host. As a result, the infection usually passes without overt clinical symptoms and develops into latent infection, referred to as "latency". During latency, the virus is maintained in a non-replicative state from which it can reactivate to productive infection under conditions of waning immune surveillance. In contrast, infection of an immunocompromised host causes CMV disease with viral multiple-organ histopathology resulting in organ failure. Primary or reactivated CMV infection of hematopoietic cell transplantation (HCT) recipients in a "window of risk" between therapeutic hemato-ablative leukemia therapy and immune system reconstitution remains a clinical challenge. Studies in the mouse model of experimental HCT and infection with murine CMV (mCMV), followed by clinical trials in HCT patients with human CMV (hCMV) reactivation, have revealed a protective function of virus-specific CD8 T cells upon adoptive cell transfer (AT). Memory CD8 T cells derived from latently infected hosts are a favored source for immunotherapy by AT. Strikingly low numbers of these cells were found to prevent CMV disease, suggesting either an immediate effector function of few transferred cells or a clonal expansion generating high numbers of effector cells. In the murine model, the memory population consists of resting central memory T cells (TCM), as well as of conventional effector-memory T cells (cTEM) and inflationary effector-memory T cells (iTEM). iTEM increase in numbers over time in the latently infected host, a phenomenon known as 'memory inflation' (MI). They thus appeared to be a promising source for use in immunotherapy. However, we show here that iTEM contribute little to the control of infection after AT, which relies almost entirely on superior proliferative potential of TCM. Immunotherapy of reactivated cytomegalovirus (CMV) infection in immunocompromised HCT recipients by adoptive transfer (AT) of antiviral CD8 T cells is the last resort to fight virus variants that have acquired resistance to standard antiviral drugs. Provision of cell numbers high enough for clearance of productive infection remains a logistical limitation for AT to become clinical routine. Although use of donor memory CD8 T cells has become the standard in clinical AT, little is known about the relative antiviral efficacies of memory CD8 T-cell activation subsets, such as central memory cells (TCM) and different populations of effector-memory cells (TEM). A reliable quantitative comparison of the antiviral efficacies of memory CD8 T-cell subsets is precluded in clinical investigation, because independent cohorts of AT donors and recipients necessarily differ in many genetic, immunologic, and virologic variables. Therefore, this is a question for which a preclinical animal model is predestined. We show here in the well-established mouse model of low-dose AT that CMV infection is by far most efficiently controlled by virus-specific TCM, due to their superior potential to proliferate even in extra-lymphoid tissue preventing intra-tissue virus spread. For clinical AT, our data provide an argument to favor transfer of TCM rather than TEM.