Ptpn22 Restricts Antiviral B cell Response by Modulating BCR Signaling

Introduction/Rationale: B cell receptor (BCR) signal strength governs effector functions that promote viral clearance. Defining how BCR signaling is regulated during infection can uncover mechanisms shaping antiviral B cell responses. Ptpn22, commonly associated with autoimmunity, encodes the immune-specific tyrosine phosphatase PEP, a proposed regulator of BCR signaling whose role remains controversial and unexplored in viral infection. PEP-deficient (PEP-null) mice infected with the chronic virus LCMV-Cl13 clear infection, whereas wild-type (PEP-WT) mice do not, suggesting PEP suppresses antiviral immunity and promotes viral persistence. However, if and how PEP may be restricting antiviral B cell function remains unknown. We hypothesize that PEP negatively regulates BCR signaling, thereby constraining B cell activation and effector function during chronic infection.

Methods: To investigate this, we first examined BCR signaling kinetics in PEP-WT and PEP-null B cells following anti-IgM stimulation by western blot. To assess downstream effects, we next used flow cytometry to profile PEP-null B cell subsets in spleen, lymph nodes, and bone marrow after various days post LCMV-cl13 infection. Finally, we evaluated PEP-null B cell function by quantifying antiviral antibody responses across infection timepoints.

Results: Key findings confirm that PEP-null B cells exhibit accelerated signaling, with earlier phosphorylation of SYK (3 min) and ERK (15 min) relative to PEP-WT. Correspondingly, PEP-null mice displayed an altered B cell landscape with increased plasmablasts and plasma cells, as well as higher anti-LCMV-Cl13 antibody titers detected up to three days earlier than PEP-WT.

Conclusion: Together, these findings demonstrate that PEP-null B cells have enhanced and accelerated BCR signaling, promoting rapid differentiation of antibody-secreting cells and elevated antibody production during chronic viral infection. This work defines a novel role for Ptpn22 and PEP in tuning BCR signaling and regulating humoral immunity.