CVR - Coronavirus Vaccines R&D Roadmap

Milestone
2.4.b

Plasma cell longevity

In progress

Identify the determinants of longevity for coronavirus antigen-specific plasma cells in bone marrow and in mucosa-associated lymphoid tissue.

Progress Highlights

APRIL (a proliferation-inducing ligand) and BAFF (B cell-activating factor) are needed for long-lived plasma cell (LLPC) maintenance.

IL-6 and CXCL12 support plasma cell longevity by interacting with the bone marrow microenvironment.

Adhesion (e.g., VCAM-1 and CXCR4) generally facilitates homing and retention of LLPCs in bone marrow niches. 

Plasma cell longevity in the bone marrow is heavily influenced by new plasma cell recruitment and niche occupancy; competition for survival niches in the marrow can dictate whether new antigen-specific plasma cells can persist long term, or be displaced by other plasma cells.

CD19−CD45+/− plasma cells is a phenotype linked to increased longevity and stability in the bone marrow.

Persistence and survival

Persistence of tissue-associated plasma cells is supported by local survival factors.

IL-5 and IL-6: Plasma cell differentiation and survival. Enhance IgA-secreting plasma cell longevity in mucosal tissues.

TGF-β: IgA class switching and retention of IgA LLPCs in the gut mucosa

APRIL and BAFF: LLPC survival in mucosal niches as well as bone marrow germinal centers

Egr1 and Bhlhe40 expression: Promotes differentiation into plasma cells over germinal center re-entry and persistence.

Mucosal homing and tissue retention mechanisms

CCR9 and α4β7 integrins: Facilitate the migration of IgA+ plasma cells to mucosal tissues.

CXCR4 and CXCR3: Promote LLPC retention within mucosal survival niches by interacting with local stromal and epithelial cells.

Persistent antigen stimulation enhances IgA+ LLPC maintenance in mucosal tissues.

Hybrid immunity elicits a more durable mucosal IgA response, supporting that LLPC survival is enhanced by repeated antigen exposure.

Mucosal booster vaccinations elicit stronger and more durable IgA+ LLPC formation.

Dhenni 2025 found that contralateral boosting favors PC differentiation over germinal center persistence.