mTOR inhibition attenuates cTfh cell dysregulation and chronic T cell activation in multi-lineage immune cytopenias.

mTOR inhibitors such as sirolimus are increasingly used in the management of children with multi-lineage immune cytopenia (m-IC). Although sirolimus is effective in improving IC, it is unclear how sirolimus affects the broader immune dysregulation associated with m-IC. We longitudinally profiled T and B cell subsets and measured cytokines and chemokines before and after sirolimus treatment. Eleven of the twelve patients with m-IC who tolerated sirolimus were followed for a median duration of 17 months. All patients had an improvement in IC and sirolimus therapy did not result in significant decreases in T, B and NK cell numbers. However, the expansion and activation of cTfh and the Th1 bias noted prior to initiation of sirolimus were significantly decreased. Features of chronic T cell activation and exhaustion within effector memory compartments of CD4+ and CD8+ T cells decreased with sirolimus therapy. Corresponding to these changes, plasma levels of CXCL9 and CXCL10 also decreased. Interestingly, no significant improvement in the proportion of class-switched memory B cells or frequencies of CD4+ naive T cells were noted. Longer follow up and additional studies are needed to validate these findings and evaluate the effect of sirolimus on B cell maturation.