Vaccine-Induced Memory CD8+ T Cells Cannot Prevent Central Nervous System Virus Reactivation

Ramakrishna, Chandran; Atkinson, Roscoe; Stohlman, Stephen A.; Bergmann, Cornelia C.

doi:10.4049/jimmunol.176.5.3062

Cited by 13 publications

(19 citation statements)

References 53 publications

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“…Inflammation, MHC class I expression, and CTL effector function wane dramatically during persistent JHMV infection (61,62). Similar effects on CTL have been observed in mice persistently infected with LCMV and humans chronically infected with HIV (63-66) and they correlate with PD-1 expression on dysfunctional CTL (67,68).…”

Section: Discussionmentioning

confidence: 73%

Structural and Biological Basis of CTL Escape in Coronavirus-Infected Mice

Butler

Theodossis

Webb

et al. 2008

The Journal of Immunology

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Cytotoxic T lymphocyte escape occurs in many human infections, as well as mice infected with the JHM strain of mouse hepatitis virus, which exhibit CTL escape variants with mutations in a single epitope from the spike glycoprotein (S510). In all CTL epitopes prone to escape, only a subset of all potential variants is generally detected, even though many of the changes that are not selected would result in evasion of the T cell response. It is postulated that these unselected mutations significantly impair virus fitness. To define more precisely the basis for this preferential selection, we combine x-ray crystallographic studies of the MHC class I (Db)/S510 complexes with viral reverse genetics to identify a prominent TCR contact residue (tryptophan at position 4) prone to escape mutations. The data show that a mutation that is commonly detected in chronically infected mice (tryptophan to arginine) potently disrupts the topology of the complex, explaining its selection. However, other mutations at this residue, which also abrogate the CTL response, are never selected in vivo even though they do not compromise virus fitness in acutely infected animals or induce a significant de novo CTL response. Thus, while structural analyses of the S510/Db complex provide a strong basis for why some CTL escape variants are selected, our results also show that factors other than effects on virus fitness limit the diversification of CD8 T cell epitopes.

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Section: Discussionmentioning

confidence: 73%

Structural and Biological Basis of CTL Escape in Coronavirus-Infected Mice

Butler

Theodossis

Webb

et al. 2008

The Journal of Immunology

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“…1) and the loss of CD8 T cell effector function following initial virus control (40, 41) raised the possibility that PD-1:B7-H1 interactions may contribute to JHMV persistence. Oligodendroglia are primary targets of viral replication during acute infection and the reservoir of persisting virus (36).…”

Section: Resultsmentioning

confidence: 99%

“…The present study examined the role of PD-1:B7-H1 interactions in contributing to immune evasion of a glialtropic coronavirus in the CNS. CD8 T cells are critical in restraining acute viral replication, yet viral RNA persists primarily in oligodendroglia, despite CD8 T cell retention within the CNS (40, 41, 57). CNS infiltrating virus-specific CD8 T cells expressed PD-1, which increased over time, even after infectious virus had been cleared from the CNS.…”

Section: Discussionmentioning

confidence: 99%

“…The failure to clear virus from oligodendroglia is not due to the absence of Ag presentation, as oligodendroglia up-regulate MHC class I and Ag processing components, albeit delayed compared to microglia (39). The observation that viral persistence in oligodendroglia is associated with persisting but non-effective CD8 T cells in the CNS (40, 41) suggests that T cell effector function may be dampened by inhibitory ligands.…”

Section: Introductionmentioning

confidence: 99%

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Target-Dependent B7-H1 Regulation Contributes to Clearance of Central Nervous Sysyem Infection and Dampens Morbidity

Phares

Ramakrishna

Parra

et al. 2009

The Journal of Immunology

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The neurotropic coronavirus JHM strain of mouse hepatitis virus persists in oligodendroglia despite the presence of virusspecific CD8 T cells. Expression of programmed death 1 (PD-1) and B7-H1 were studied during acute and persistent infection to examine whether this negative regulatory mechanism contributes to CNS viral persistence. The majority of CNS-infiltrating CD8 T cells expressed PD-1, with the highest levels on virus-specific CD8 T cells. Moreover, despite control of infectious virus, CD8 T cells within the CNS of persistently infected mice maintained high PD-1 expression. Analysis of virus-susceptible target cells in vivo revealed that B7-H1 expression was regulated in a cell type-dependent manner. Oligodendroglia and microglia up-regulated B7-H1 following infection; however, although B7-H1 expression on oligodendroglia was prominent and sustained, it was significantly reduced and transient on microglia S everal features of the CNS make it a challenging environment for the immune response to efficiently clear virus. These obstacles include the blood-brain barrier, a specialization of the vasculature in the CNS that limits leukocyte entry (1). In addition, the absence of classical lymphoid drainage and restricted Ag presentation by CNS resident cells hinders induction, recruitment, and retention of adaptive immune cells. Furthermore, in contrast to peripheral infections, several target cells of CNS infections are terminally differentiated, nonrenewable cells which have evolved mechanisms to avoid extensive immune-mediated damage. However, the same mechanisms protecting CNS resident cells from extensive immune-mediated pathology also favor establishment of viral persistence.A variety of inhibitory molecules and their ligands on T cells and infected cells contribute to T cell dysfunction, thereby fostering viral persistence. Among these are the programmed death 1 (PD-1) 5 receptor and its ligand B7-H1, also known as PD-L1, which belong to the B7:CD28 family (2). PD-1 is inducibly expressed on T cells, B cells (3), monocytes (4), and NK cells (5). B7-H1 is constitutively expressed on T cells, B cells, macrophages, and dendritic cells and is further up-regulated after stimulation (6, 7). B7-H1 is also expressed on a variety of nonhematopoietic cell types including vascular endothelial cells (8), epithelial cells (9), and cells of the nervous system (10 -13). PD-1:B7-H1 interactions trigger a noneffective T cell response, referred to as "T cell exhaustion," which is characterized by impaired proliferation, cytolysis, and cytokine production (8, 9, 14 -24). Exhausted T cells were initially described in chronic lymphocytic choriomeningitis virus-infected mice (24) and similar dysfunction of T cells has been reported during HIV (19, hepatitis C virus (15,26,27)-, and simian immunodeficiency virus (28)-persistent infections. Similar to pathogens exploiting the PD-1:B7-H1 pathway to establish persistence, expression of B7-H1 on tumors may also serve as an immune evasion strategy (29,30).The role of inhibitory mol...

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“…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).…”

Section: -Discussionmentioning

confidence: 99%