Programming isotype specific plasma cell differentiation

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. Using integrated single cell strategies, we reveal conserved and divergent components of the rapid effector phase of antigen-specific IgM+ versus inflammation modulating programs dictated by IgG2a/b+ PC differentiation. During antibody affinity maturation, the germinal center (GC) cycle imparts separable programs for post-GC inhibitory IgG1+ and 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 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.

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Affinity maturation for an optimal balance between long-term immune coverage and short-term resource constraints

10.1101/2021.07.26.453765 ◽

2021 ◽

Author(s):

Victor Chardes ◽

Massimo Vergassola ◽

Aleksandra M Walczak ◽

Thierry Mora

Keyword(s):

Immune System ◽

Resource Constraints ◽

Affinity Maturation ◽

Optimal Decision ◽

Immune Protection ◽

Short Term ◽

Cell Repertoire ◽

Memory Pool ◽

Metabolic Costs

In order to target threatening pathogens, the adaptive immune system performs a continuous reorganization of its lymphocyte repertoire. Following an immune challenge, the B cell repertoire can evolve cells of increased specificity for the encountered strain. This process of affinity maturation generates a memory pool whose diversity and size remain difficult to predict. We assume that the immune system follows a strategy that maximizes the long-term immune coverage and minimizes the short-term metabolic costs associated with affinity maturation. This strategy is defined as an optimal decision process on a finite dimensional phenotypic space, where a pre-existing population of naive cells is sequentially challenged with a neutrally evolving strain. We unveil a trade-off between immune protection against future strains and the necessary reorganization of the repertoire. This plasticity of the repertoire drives the emergence of distinct regimes for the size and diversity of the memory pool, depending on the density of naive cells and on the mutation rate of the strain. The model predicts power-law distributions of clonotype sizes observed in data, and rationalizes antigenic imprinting as a strategy to minimize metabolic costs while keeping good immune protection against future strains.

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Adjuvant-specific regulation of long-term antibody responses by ZBTB20

Journal of Experimental Medicine ◽

10.1084/jem.20131821 ◽

2014 ◽

Vol 211 (5) ◽

pp. 841-856 ◽

Cited By ~ 47

Author(s):

Yinan Wang ◽

Deepta Bhattacharya

Keyword(s):

Antibody Production ◽

Plasma Cells ◽

Fetal Liver ◽

Serum Antibody ◽

Cell Formation ◽

Affinity Maturation ◽

Wild Type ◽

Transgenic Expression ◽

Specific Regulation

The duration of antibody production by long-lived plasma cells varies with the type of immunization, but the basis for these differences is unknown. We demonstrate that plasma cells formed in response to the same immunogen engage distinct survival programs depending on the adjuvant. After alum-adjuvanted immunization, antigen-specific bone marrow plasma cells deficient in the transcription factor ZBTB20 failed to accumulate over time, leading to a progressive loss of antibody production relative to wild-type controls. Fetal liver reconstitution experiments demonstrated that the requirement for ZBTB20 was B cell intrinsic. No defects were observed in germinal center numbers, affinity maturation, or plasma cell formation or proliferation in ZBTB20-deficient chimeras. However, ZBTB20-deficient plasma cells expressed reduced levels of MCL1 relative to wild-type controls, and transgenic expression of BCL2 increased serum antibody titers. These data indicate a role for ZBTB20 in promoting survival in plasma cells. Strikingly, adjuvants that activate TLR2 and TLR4 restored long-term antibody production in ZBTB20-deficient chimeras through the induction of compensatory survival programs in plasma cells. Thus, distinct lifespans are imprinted in plasma cells as they are formed, depending on the primary activation conditions. The durability of vaccines may accordingly be improved through the selection of appropriate adjuvants.

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Germinal center B cells govern their own fate via antibody feedback

Journal of Experimental Medicine ◽

10.1084/jem.20120150 ◽

2013 ◽

Vol 210 (3) ◽

pp. 457-464 ◽

Cited By ~ 143

Author(s):

Yang Zhang ◽

Michael Meyer-Hermann ◽

Laura A. George ◽

Marc Thilo Figge ◽

Mahmood Khan ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Plasma Cells ◽

Large Range ◽

Cell Interaction ◽

Affinity Maturation ◽

Antibody Affinity ◽

Random Mutation ◽

Efficient Selection ◽

Selection Of

Affinity maturation of B cells in germinal centers (GCs) is a process of evolution, involving random mutation of immunoglobulin genes followed by natural selection by T cells. Only B cells that have acquired antigen are able to interact with T cells. Antigen acquisition is dependent on the interaction of B cells with immune complexes inside GCs. It is not clear how efficient selection of B cells is maintained while their affinity matures. Here we show that the B cells’ own secreted products, antibodies, regulate GC selection by limiting antigen access. By manipulating the GC response with monoclonal antibodies of defined affinities, we show that antibodies in GCs are in affinity-dependent equilibrium with antibodies produced outside and that restriction of antigen access influences B cell selection, seen as variations in apoptosis, plasma cell output, T cell interaction, and antibody affinity. Feedback through antibodies produced by GC-derived plasma cells can explain how GCs maintain an adequate directional selection pressure over a large range of affinities throughout the course of an immune response, accelerating the emergence of B cells of highest affinities. Furthermore, this mechanism may explain how spatially separated GCs communicate and how the GC reaction terminates.

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