Checkpoint control of T cell-B cell collaboration in the regulation of autoimmunity

Immune checkpoint drugs that unleash T cells against tumours can also trigger autoimmune side effects, and a team at the University of Oxford has now traced the problem to a specific subset of immune cells called follicular helper T cells (Tfh). These drugs—antibodies that block proteins like CTLA-4 and PD-1—are designed to remove the brakes on the immune system so it attacks cancer. But in some patients, the same mechanism causes the immune system to attack healthy tissue. The researchers have shown in mice that blocking CTLA-4 spontaneously drives Tfh differentiation, a process that normally helps B cells produce antibodies. Because Tfh cells are already overrepresented in autoimmune diseases like lupus and rheumatoid arthritis, the team suspects that checkpoint inhibitors may inadvertently trigger autoimmunity by pushing T cells into this Tfh pathway. This project will test whether Tfh induction is a general feature of autoimmunity, and whether Tfh populations can predict disease outcomes—both in classical autoimmune conditions and in patients suffering side effects from checkpoint inhibitors. The work is fundamental science, exploring how two checkpoint proteins, CTLA-4 and PD-1, cooperate to regulate Tfh differentiation. If successful, it could lead to biomarkers that identify patients at risk of autoimmune complications before they start cancer immunotherapy, or inform strategies to separate the anti-tumour effects of checkpoint blockade from its unwanted immune reactions.