CBL and CBL-B Restrain Tfh Cell Responses and Systemic Lupus Erythematosus by Facilitating BCL-6 Degradation via the Chaperone-Mediated Autophagy

Hyper Tfh cell responses have been linked to some SLE patients; however, molecular traits leading to the abnormal Tfh cell homeostasis and SLE remains elusive. Li et al. show here that a cohort of active SLE patients simultaneously downregulate CBL and CBL-B (CBLs) in CD4+ T cells and have increased blood circulating Tfh (cTfh) cells which upregulate ICOS and BCL6. Ablation of CBLs in mouse T cells also leads to hyper Tfh cell responses and manifestation of SLE. They further show that under the normal circumstance BCL6 is degraded via chaperone-mediated autophagy (CMA), and this process is oppositely regulated by ICOS-AKT signaling and ICOS ubiquitination mediated by CBLs. Since CBLs also restrains human Tfh cell responses by the same regulatory mode, downregulation of CBLs in human T cells likely to be causative to development of SLE in humans. Overall design: To investigate the influence of the ICOS-CBLs signalling axis on the Tfh cell developmental program