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 immunothera-peutic applications and vaccine design.
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