Programming Isotype-Specific Plasma Cell Function

Abstract

Helper T cell induced plasma cells (PCs) that secrete class-switched neutralizing antibody are paramount to effective immunity. Following class-switch recombination (CSR), antigen-activated B cells differentiate into extrafollicular PCs or mature in germinal centers (GCs) to produce high-affinity memory B cells and follicular PCs. Many studies focus on the core transcriptional programs that drive central PC functions of longevity and antibody secretion. However, it is becoming clear that these central programs are further subdivided across antibody isotype with separable transcriptional trajectories. Divergent functions emerge at CSR, persist through PC terminal differentiation and further assort memory PC function following antigen recall. Here, we emphasize recent work that assorts divergent isotype-specific PC function across four major modules of immune protection.

Keywords: B cell memory; follicular T helper; isotype; plasma cell.

Figure 1:. Plasma cells derive from three distinct pathways.

A schematic representation of plasma cell (PC) formation pathways is shown. Naïve B cells can be directly activated by antigen and undergo class switch recombination (CSR) without T cell help, forming unmutated PCs. Alternately, T helper (T_H) cells can activate B cells through cognate contact, and direct CSR via secreted factors. Higher antigen affinity B cells are directed to form extrafollicular PCs while lower affinity B cells can enter a germinal center (GC) reaction. GC B cells undergo iterative rounds of somatic hypermutation under the direction of follicular T helper cells (T_FH). B cells with highest affinity are selected for survival, exiting the GC as memory B cells and follicular PCs. T cell help and CSR likely imprint distinct transcriptional programs that can influence B cell fate and function.

Figure 2:. CD4⁺ Helper T (T_H) cell subsets have varied immune protection roles.

Naïve CD4⁺ T cells differentiate into T_H cell subsets under the direction of environmental factors that influence the expression of specific lineage defining master transcription factors. These transcription factors induce transcriptional programming leading to unique effector functions, such as cytokine secretion for each T_H cell subset. Abbreviations: Foxp3, forkhead box protein 3; Gata3, GATA-binding factor 3; IFNγ, Interferon gamma; RORγ, retinoid-related orphan receptor gamma; Stat1, Signal transducer and activator of transcription 1; Stat3, Signal transducer and activator of transcription 3; Stat6, Signal transducer and activator of transcription 6; TGF-β, transforming growth factor-β; TH1, T-helper-1; TH2, T-helper-2; TH17, T-helper-17; TNFα, Tumor necrosis factor alpha; TREG, regulatory T.

Key Figure, Figure 3:. Plasma cell isotype defines effector function heterogeneity.

Helper T (T_H) cell derived factors specifically elicit class switch recombination (CSR) in B cells to certain isotypes. Both T cell help and CSR likely imprint distinct transcriptional programs that influence B cell lineage fate and function, and which are maintained through terminal differentiation. As emphasized by terminally differentiated plasma cells, B cell isotypes participate in discrete immune responses through secreted cytokines and antibodies. B cell immunity can therefore be assorted into the four major categories of immunity used for T_H and innate lymphoid cell subsets: type I inflammatory, type II anti-inflammatory, type III mucosal, and regulatory immunity (herein described as type IV). Abbreviations: IFNγ, Interferon gamma; RA, Retinoic acid; TGF-β, transforming growth factor-β