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

Productive communication between T cells and B cells is vital for protective immunity, however dysregulation of this process can trigger autoimmunity.

Costimulatory checkpoints limit T cell help for B cells by controlling the differentiation of follicular helper T cells (Tfh), a cellular subset overrepresented in multiple autoimmune diseases. We have found that anti-CTLA-4 antibodies can trigger spontaneous Tfh differentiation in mice.

Targeting CTLA-4 with checkpoint inhibitors in cancer patients may therefore induce Tfh, potentially relevant to the autoimmune side-effects seen with these treatments.

Despite their escalating clinical burden, the cellular mechanisms underpinning checkpoint-inhibitor induced autoimmunity remain poorly understood.

In this proposal I will investigate the hypothesis that induction of Tfh responses is a general feature of autoimmunity, reflecting a loss of costimulatory (checkpoint) control.

I will explore how CTLA-4 and PD-1 co-operate to regulate Tfh differentiation, and establish the consequence of a Tfh response for tissue autoimmunity.

Insights will be drawn from autoimmune patients treated with CTLA-4-Ig, and cancer patients treated with CTLA-4 antibodies.

Building on exciting preliminary data, I will determine whether Tfh populations have value in predicting outcomes in classical autoimmunity as well as in checkpoint-inhibitor induced disease.