Ptpn2 limits plasma cell fate and antiviral immunity by integrating B cell receptor and IFN-γ signals in B cells.

Abstract

Antigen-specific humoral responses are critical for long-term protection against infectious diseases, yet the mechanisms that regulate B cell differentiation and antibody production remain incompletely defined. Here, we identify the Protein Tyrosine Phosphatase Nonreceptor Type 2 (Ptpn2) as a B cell-intrinsic regulator of plasma cell fate and isotype switching. Using a B cell-specific Ptpn2 knockout mouse model, we show that Ptpn2 restrains both B cell receptor and interferon-γ (IFN-γ) signaling by directly dephosphorylating Lyn, STAT1, and STAT3. Loss of Ptpn2 leads to hyperactivation of these two signaling pathways, resulting in transcriptional reprogramming that promotes plasma cell differentiation and increased IFN-γ-driven antibody production. Functionally, Ptpn2-deficient mice generated enhanced primary antiviral antibody responses following influenza infection and elevated virus-specific and neutralizing titers upon recall without compromising affinity. These findings identify Ptpn2 as a key intracellular checkpoint that integrates antigenic and inflammatory cues to regulate humoral immunity, with potential implications for enhancing vaccine-induced protective immunity.