The biochemical characterization of the effects of phospho-Ser449 on early TCR signaling, coupled with the assessment of KI mice, uncovered previously unreported PTPN22-controlled retrograde feedback loop, which is activated by ZAP70 and impairs dephosphorylation of LCK Tyr192 by CD45, thus promoting TCR signaling and autoimmunity. Here, LCK is linked to Autoimmunity.