Altered marginal zone and innate-like B cells in aged senescence-accelerated SAMP8 mice with defective IgG1 responses

Abstract

Aging has a strong impact on the activity of the immune system, enhancing susceptibility to pathogens and provoking a predominant pre-inflammatory status, whereas dampening responses to vaccines in humans and mice. Here, we demonstrate a loss of marginal zone B lymphocytes (MZ, CD19⁺CD45R⁺CD21⁺⁺CD23^lo) and a decrease of naive B cells (CD19⁺IgD⁺), whereas there is an enhancement of a CD19⁺CD45R^lo innate-like B cell population (B1REL) and the so-called aged B cell compartment (ABC, CD45R⁺CD21^loCD23^loCD5^-CD11b^-) in aged senescence-accelerated (SAMP8) mice but not in aged senescence-resistant (SAMR1) mice. These changes in aged SAMP8 mice were associated with lower IgG isotype levels, displaying low variable gene usage repertoires of the immunoglobulin heavy chain (V_H) diversity, with a diminution on IgG1-memory B cells (CD11b^-Gr1^-CD138^-IgM^-IgD^-CD19⁺CD38⁺IgG1⁺), an increase in T follicular helper (T_FH, CD4⁺CXCR5⁺PD1⁺) cell numbers, and an altered MOMA-1 (metallophilic macrophages) band in primary follicles. LPS-mediated IgG1 responses were impaired in the B1REL and ABC cell compartments, both in vitro and in vivo. These data demonstrate the prominent changes to different B cell populations and in structural follicle organization that occur upon aging in SAMP8 mice. These novel results raise new questions regarding the importance of the cellular distribution in the B cell layers, and their effector functions needed to mount a coordinated and effective humoral response.