M11
‐
CAR
T cells inhibit murine cytomegalovirus
in vitro
upon recognition of virion‐ and cell‐associated glycoprotein B
Sabrina Kübel, Christopher Garçon, Hanna Menschikowski, Arne Cordsmeier, Jens‐Christian Albrecht, Friederike Oltmanns, Larissa Bauer, Manuel Hermann, Kristina Holdt, Heinrich Sticht, Marco Thomas, Thomas H Winkler, Brigitte Scholz, Doris Jungnickl, Armin Ensser Abstract
Objectives
Viral infections are predominantly managed with conventional antiviral drugs, which, despite their efficacy, can cause toxicity and promote resistance. Cell‐based immunotherapies offer an alternative, but cytomegaloviruses (CMV) profoundly interfere with MHC class I antigen presentation, thereby impairing conventional virus‐specific T‐cell responses towards infected cells. We therefore aimed to develop an MHC‐unrestricted CAR T‐cell approach for CMV infection and investigate its antiviral activity.
Methods
We generated M11‐CAR, a fully murine, second‐generation CAR based on the M11 monoclonal antibody targeting glycoprotein B (gB) of murine CMV (MCMV). Primary splenocytes were transduced to assess CAR functionality following ectopic gB expression or MCMV infection. T‐cell cytotoxicity, cytokine production and antiviral activity were evaluated and compared with human CD19‐specific control CAR T cells.
Results
M11‐CAR T cells specifically recognized gB following ectopic expression and MCMV infection, inducing cytotoxicity and cytokine production. CAR‐mediated cytokine production, particularly interferon‐γ, translated into robust MCMV inhibition. Increasing MCMV loads impaired cytokine responses of CD19‐CAR T cells, whereas M11‐CAR T cells maintained strong responses. This effect was partially attributable to direct recognition of virion‐associated gB, resulting in activation of M11‐CARs.
Conclusions
M11‐CAR T cells enable MHC‐independent recognition of MCMV, providing a potential strategy to circumvent CMV‐mediated disruption of antigen presentation and immune recognition. Our findings demonstrate that virions can directly shape virus‐specific CAR T‐cell responses and highlight the importance of antigen recognition mechanisms that are independent of MHC presentation. This provides a basis for refining CAR designs for persistent viral infections characterized by immune evasion.