Research Article: Systemic Hematogenous Maintenance of Memory Inflation by MCMV Infection

Date Published: July 3, 2014

Publisher: Public Library of Science

Author(s): Corinne J. Smith, Holly Turula, Christopher M. Snyder, Chris A. Benedict.


Several low-grade persistent viral infections induce and sustain very large numbers of virus-specific effector T cells. This was first described as a response to cytomegalovirus (CMV), a herpesvirus that establishes a life-long persistent/latent infection, and sustains the largest known effector T cell populations in healthy people. These T cells remain functional and traffic systemically, which has led to the recent exploration of CMV as a persistent vaccine vector. However, the maintenance of this remarkable response is not understood. Current models propose that reservoirs of viral antigen and/or latently infected cells in lymph nodes stimulate T cell proliferation and effector differentiation, followed by migration of progeny to non-lymphoid tissues where they control CMV reactivation. We tested this model using murine CMV (MCMV), a natural mouse pathogen and homologue of human CMV (HCMV). While T cells within draining lymph nodes divided at a higher rate than cells elsewhere, antigen-dependent proliferation of MCMV-specific effector T cells was observed systemically. Strikingly, inhibition of T cell egress from lymph nodes failed to eliminate systemic T cell division, and did not prevent the maintenance of the inflationary populations. In fact, we found that the vast majority of inflationary cells, including most cells undergoing antigen-driven division, had not migrated into the parenchyma of non-lymphoid tissues but were instead exposed to the blood supply. Indeed, the immunodominance and effector phenotype of inflationary cells, both of which are primary hallmarks of memory inflation, were largely confined to blood-localized T cells. Together these results support a new model of MCMV-driven memory inflation in which most immune surveillance occurs in circulation, and in which most inflationary effector T cells are produced in response to viral antigen presented by cells that are accessible to the blood supply.

Partial Text

Cytomegaloviruses (CMVs) are ubiquitous, β-herpesviruses that establish lifelong infections in their hosts. CMV causes an acute systemic viral infection, followed by latency in many cells throughout the body. Cells of the myeloid lineage and endothelial cells from many organs have been shown to harbor CMV[1]–[17]. However, the sites of viral latency have not been fully defined, largely because it is extremely difficult to detect the virus during latency. Latent CMV is thought to reactivate in a stochastic manner throughout the body[18], [19]. Thus, keeping CMV asymptomatic requires a robust immune surveillance effort by NK cells and virus-specific CD4 and CD8 T cells[20]. For this reason, immune compromised individuals are at great risk of CMV reactivation[21]. Importantly, CMV-specific CD8 T cells directly suppress viral gene expression during this latent/persistent phase of infection[22] and can, in isolation, control CMV replication[23]–[26].

Memory inflation is a unique immune response that provides continuous immune surveillance against a lifelong infection without inducing T cell exhaustion[27], [29], [31], [42], [43], [65], [66]. However the mechanism that supports memory inflation has not been well defined. Our previous data support the model that memory inflation during MCMV infection is maintained by systemic antigen-dependent production of short-lived effectors[43]. Here, we show that T cell division originating in the lymph nodes, as well as the migration of T cells through lymph nodes, was completely dispensable for the long-term maintenance of these effector populations. Furthermore, our data show that the bulk of inflationary CD8s that appear to be “in” organs are part of a circulating population with access to the blood, with only a small minority residing within non-lymphoid organs at any given time during the late stages of infection. Indeed, the immunodominance profile and effector phenotype that are characteristic of memory inflation were primarily evident in the blood-localized compartment and not within cells that were shielded from the blood supply. These data lead us to propose a new model of memory inflation in which the effector T cell populations are primarily produced by exposure to antigen that is accessible to the blood supply and are subsequently maintained in circulation.




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