Adoptive immunotherapy induces CNS dendritic cell recruitment and antigen presentation during clearance of a persistent viral infection

Abstract

Given the global impact of persistent infections on the human population, it is of the utmost importance to devise strategies to noncytopathically purge tissues of infectious agents. The central nervous system (CNS) poses a unique challenge when considering such strategies, as it is an immunologically specialized compartment that contains a nonreplicative cell population. Administration of exogenously derived pathogen-specific memory T cells (referred to as adoptive immunotherapy) to mice burdened with a persistent lymphocytic choriomeningitis virus (LCMV) infection from birth results in eradication of the pathogen from all tissues, including the CNS. In this study, we sought mechanistic insights into this highly successful therapeutic approach. By monitoring the migration of traceable LCMV-specific memory CD8+ T cells after immunotherapy, it was revealed that cytotoxic T lymphocytes (CTLs) distributed widely throughout the CNS compartment early after immunotherapy, which resulted in a dramatic elevation in the activity of CNS antigen-presenting cells (APCs). Immunotherapy induced microglia activation as well as the recruitment of macrophages and dendritic cells (DCs) into the brain parenchyma. However, DCs emerged as the only CNS APC population capable of inducing memory CTLs to preferentially produce the antiviral cytokine tumor necrosis factor-α, a cytokine demonstrated to be required for successful immunotherapeutic clearance. DCs were also found to be an essential element of the immunotherapeutic process because in their absence, memory T cells failed to undergo secondary expansion, and viral clearance was not attained in the CNS. These experiments underscore the importance of DCs in the immunotherapeutic clearance of a persistent viral infection and suggest that strategies to elevate the activation/migration of DCs (especially within the CNS) may facilitate pathogen clearance.

High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation

“…Bearing early-activated T-lymphocyte and dendritic cell markers, CRMP2hi cells could comprise active cytolytic CD8+ T-lymphocytes, regulatory CD4+ T cells and antigen-presenting cells, each displaying their own role. They could therefore be crucial either in controlling the immune response to pathogens and virus clearance or in preventing reactivity to self-antigens, thus reducing the autoimmune reaction within the CNS (Serafini et al, 2004;Serafini et al, 2006;Esiri, 2007;Lauterbach et al, 2006;Ramakrishna et al, 2006). lymphocytes infiltrated in CDV-infected brain structures hippocampus, thalamus and at proximity of the blood-CNS (velum interpositum) and CSF-CNS (third ventricle) interfaces (avidiin-biotin peroxidase system) (microscope field x100 and x400).…”

Lymphocytic choriomeningitis infection of the central nervous system

“…Each of these cytokines were shown be required for viral clearance following immunotherapy (107,119,122). A recent study examining mice 8 days post-immunotherapy revealed that a considerable number of antigen presenting cells (APCs) were recruited into the CNS of carrier mice as a direct consequence of the immunotherapy, and this APC recruitment correlated perfectly with the arrival of LCMV-specific CTL (107).…”

“…Oldstone and colleagues demonstrated that LCMV was purged from peripheral tissues (e.g., serum, liver, lungs and spleen) by day 15 post-immunotherapy but persisted in the brain and kidney of carrier mice until around day 120 (116). Although initial studies of brain tissues after immunotherapy demonstrated a restriction of infiltrates to the leptomeninges with little to no inundation of the brain parenchyma (116,126), a more sensitive assay revealed that GFPtagged LCMV-specific CTL distribute evenly throughout the brain parenchyma within 8 days following immunotherapy (107). Interestingly, LCMV clearance from neurons in carrier mice occurs with minimal neuronal drop out, suggesting a noncytopathic mechanism of clearance (116,126).…”

“…Each of these cytokines were shown be required for viral clearance following immunotherapy (107,119,122). A recent study examining mice 8 days post-immunotherapy revealed that a considerable number of antigen presenting cells (APCs) were recruited into the CNS of carrier mice as a direct consequence of the immunotherapy, and this APC recruitment correlated perfectly with the arrival of LCMV-specific CTL (107). Importantly, of the APC subsets only dendritic cells (not infiltrating macrophages or resident microglia) were able to stimulate LCMV-specific CTL to produce IFNγ and TNFα production, and immunological synapses between CTL and APCs were observed in situ (84).…”

Cutting Edge: Cross-Presented Intracranial Antigen Primes CD8+ T Cells

“…1). Within the CNS, DCs remain the best candidate for the APC responsible for the capture and crosspresentation of brain Ag (4,6,15). As our experimental model explored only situations of brain inflammation secondary to the injection of Ag, both resident and infiltrating DCs are candidates for the responsible APC (8,16,17).…”