Research paperNon-cognate bystander cytolysis by clonal epitope-specific CTL lines through CD28-CD80 interaction inhibits antibody production: A potential caveat to CD8 T-cell immunotherapy

- Clonal epitope-specific CTL can lyse target cells without TCR engagement.
- Non-cognate cytolysis is mediated through CD28-CD80 interaction.
- Non-cognate cytolysis does not involve perforin or Fas-FasL signaling.
- Bystander cytolysis of CD80+ B-cell blasts inhibits antibody production.
- Cytoimmunotherapy with CTL may cause cell type-selective immunopathogenesis.

Adoptive transfer of virus epitope-specific CD8 T cells is an immunotherapy option to control cytomegalovirus (CMV) infection and prevent CMV organ disease in immunocompromised solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT) recipients. The therapy aims at an early, selective recognition and cytolysis of infected cells for preventing viral spread in tissues with no adverse immunopathogenic side-effects by attack of uninfected bystander cells. Here we describe that virus epitope-specific, cloned T-cell lines lyse target cells that present the cognate antigenic peptide to the TCR, but simultaneously have the potential to lyse uninfected cells expressing the CD28 ligand CD80 (B7-1). While TCR-mediated cytolysis requires co-receptor CD8 and depends on perforin, the TCR-independent and viral epitope-independent cytolysis through CD28-CD80 signaling does not require CD8 on the effector cells and is perforin-independent. Importantly, this non-cognate cytolysis pathway leads to bystander cytolysis of CD80-expressing B-cell blasts and thereby inhibits pan-specific antibody production.

TCR-dependent and CD28-dependent target cell killing exerted simultaneously by cloned epitope-specific CTL.