Isotype-specific plasma cells express divergent transcriptional programs

Antibodies are produced across multiple isotypes with distinct properties that coordinate initial antigen clearance and confer long-term antigen-specific immune protection. Here, we interrogate the molecular programs of isotype-specific murine plasma cells (PC) following helper T cell-dependent immunization and within established steady-state immunity. We developed a single-cell-indexed and targeted molecular strategy to dissect conserved and divergent components of the rapid effector phase of antigen-specific IgM(+) versus inflammation-modulating programs dictated by type 1 IgG2a/b(+) PC differentiation. During antibody affinity maturation, the germinal center (GC) cycle imparts separable programs for post-GC type 2 inhibitory IgG1(+) and type 1 inflammatory IgG2a/b(+) PC to direct long-term cellular function. In the steady state, two subsets of IgM(+) and separate IgG2b(+) PC programs clearly segregate from splenic type 3 IgA(+) PC programs that emphasize mucosal barrier protection. These diverse isotype-specific molecular pathways of PC differentiation control complementary modules of antigen clearance and immune protection that could be selectively targeted for immunotherapeutic applications and vaccine design.