Dissecting T-cell immunity to JCV to design novel predictive tools and therapies for PML

Principle Investigator

Scientific interest within the context of the graduate college

This project aligns with Re-Thinking Health by investigating homeostatic immune control of a common virus, the John Cunningham virus (JCV), by deciphering the identity and function of rare populations of protective T-cells in preventing JCV reactivation and progressive multifocal leukoencephalopathy (PML). Up to 80-90% of all adults are infected with JCV, but the infection rarely causes disease. In contrast, individuals with compromised T cell immunity are at risk of PML, with high mortality and limited treatment options. Resolving antigenic targets and functional identity of protective T-cell responses, will enable design of novel vaccines and enable a more precise risk prediction in at-risk populations, such as patients under immune suppressive therapies. The program’s focus on health as an active regulated biological state, together with its emphasis on prevention-oriented translational research, provides an ideal framework to investigate adaptive immune mechanisms underlying latent viral control and maintenance of organismal health.

Project description

Human polyomaviruses are a family of DNA viruses that primarily establish persistent asymptomatic infections but can reactivate into virulent archetypes under conditions of immunosuppression. One such example is JCV, which exhibits tropism for oligodendrocytes in the central nervous system (CNS) upon reactivation, leading to the development of PML. PML is a rare but often fatal demyelinating disease of the CNS, with no licensed treatment options available to-date. Interventions including immune checkpoint inhibitors have yielded heterogenous response rates, and restoration of JCV-specific T-cell immunity currently remains the single most effective strategy to control CNS viral load and PML. Yet, this is not always possible, leaving a high unmet clinical need to better treat this debilitating disease.

While recent advances have opened promising opportunities for treatment of active PML, such as immune checkpoint blockade or adoptive T-cell transfer, our basic understanding of antigen specificity and functional capacity of protective T-cell immunity against PML remains surprisingly limited. This gap is largely attributable to technical challenges associated with detecting JCV-specific T-cells, which are present at exceptionally low frequencies in the periphery of healthy individuals, despite effective immune control. This hinders effective design of predictive assays for individuals under immunosuppression and also represents a barrier to identify protective T cells, TCRs, and their cognate epitopes profile; thus, posing a major roadblock in preventing and treating JCV reactivation and disease (PML).

To address this, we have previously i) developed a highly sensitive assay to detect rare JCV-specific CD4 T-cells from donor and patient derived peripheral blood, and ii) established a platform to isolate antigen-specific T-cell clones, and analyze their TCR and the cognate peptide epitopes, and extract transcriptomic signatures at single cell resolution. We are currently validating a sizeable set of CD4 TCR and peptide pairs. In the proposed project, we aim to extend this methodology to identify CD8 T cells, their TCRs, and MHC-I restricted epitopes. This will not only yield critical insights into JCV immune control, but it will provide a blueprint to study T cell dependent immune control to chronic viruses and build valuable datasets for machine learning based prediction of TCR – peptide pairing.

Aim 1. Adapt and validate T cell detection assay of JCV-specific CD8 T-cells.

Aim 2. Uncover JCV-specific CD8 T-cell clones, TCRs, their transcriptional profile and their cognate epitopes.

Aim 3. Validate the identified viral epitopes and TCRs by re-expression of TCRs.

Taken together, the proposed project will shed new light on immune control of JCV. Uncovered T-cell epitopes and TCRs present an attractive basis for the development of patient-specific cellular precision therapies.

Application details

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