Immune reset after deep B-lineage depletion: remission is not reprogramming

Deep B-lineage-depleting therapies, including chimeric antigen receptor (CAR) T cells and T-cell engagers, can induce prolonged drug-free remissions in patients with refractory systemic autoimmune diseases, prompting deep depletion and 'immune reset' as an emerging therapeutic paradigm. However, durable clinical improvement does not by itself establish immune reset, which implies elimination of autoreactive memory and reconstitution of a renewed, self-tolerant immune repertoire. Furthermore, biological evidence for immune reset following CAR T-cell therapies remains limited to date. In this viewpoint, we aim to address what evidence is required before a mechanistic claim of immune reset can be justified. We propose a provisional research agenda that separates clinical outcomes from target-compartment depletion, humoral reconfiguration, molecular quiescence and complete 'immune reset'. Full 'immune reset' should be defined operationally as durable restoration of self-tolerance despite persistent genetic susceptibility and other contributing pathogenic factors, supported by concordant evidence across disease-relevant tissues, B- and T-cell memory, functional antigen specificity and immune reconstitution. Current data are insufficient to establish this state in most patients.