TFH cells isolated from mice and humans with autoimmune disease exhibit transcriptional and functional changes. We propose that loss of GC tolerance is due to TFH dysregulation, albeit through various mechanisms of dysfunction. TFH cells might permit or promote autoreactive B cell development due to dysregulated transcription factor expression, cytokine and chemokine profiles, co-stimulation, metabolism, exhaustion, and trafficking. GC, germinal center; TFH, follicular helper T cell.