The immunology of B-1 cells: from development to aging

Abstract

B-1 cells have intricate biology, with distinct function, phenotype and developmental origin from conventional B cells. They generate a B cell receptor with conserved germline characteristics and biased V(D)J recombination, allowing this innate-like lymphocyte to spontaneously produce self-reactive natural antibodies (NAbs) and become activated by immune stimuli in a T cell-independent manner. NAbs were suggested as "rheostats" for the chronic diseases in advanced age. In fact, age-dependent loss of function of NAbs has been associated with clinically-relevant diseases in the elderly, such as atherosclerosis and neurodegenerative disorders. Here, we analyzed comprehensively the ontogeny, phenotypic characteristics, functional properties and emerging roles of B-1 cells and NAbs in health and disease. Additionally, after navigating through the complexities of B-1 cell biology from development to aging, therapeutic opportunities in the field are discussed.

Keywords: Aging; Autoantibodies; B cell development; B-1 cell; Immunology; Natural antibody.

Fig. 1

Key molecular events in B-1 cell development. B cell lymphopoiesis takes place in three waves. The first wave starts at E9.0 at the yolk sac. This wave is HSCs-independent and generates only B-1 cells. The second wave takes place in the FL, it is HSCs-dependent and can generate mainly B-1 but also B-2 cells while the third wave happens in the adult BM and mainly generates B-2 cells. (A) Lin28b is responsible to downregulate the micro–RNA Let-7 which normally prevents the activation of the transcriptional factor Arid3a. Activated Arid3a can migrate to the nucleus and bias the choice of V_H during VDJ recombination. (B) Additionally, Arid3a can be palmitoylated in the cytoplasm and associate with BCR-containing lipid rafts, increasing the threshold required for BCR activation. (C) Bhlhe41 regulates the expression of the α-chain of the IL-5 receptor. (D) IL-5R signaling is required for B-1 cell proliferation and self-renewal. (E) PU.1 controls the expression of key genes in B-1 cell development such as IL-7Ra, Pax5 and Flt3. (F) CTLA4 is essential for the stability of the BCR and to control B-1 cell proliferation. (G) Absence of IL-7 signaling prevents pSTAT5-mediated inhibition of Ig_K recombination in FL

Fig. 2

B-1 cell migration and tissue distribution. Progenitor B-1 cells (Lin⁻ CD93⁺ CD19⁺ B220^low) migrate from FL to the neonate spleen where they can be found as transitional B-1 cells (IgM⁺ CD19⁺ CD23^± CD93⁺) until the second week of life. At this moment, transitional B-2 cells starts to arrive in the spleen and the transitional B-1 cells migrates to the body cavities where they arrive trough the omentum and can be found as mature B-1 cells (IgM^high IgD^low CD19^high B220^low CD23⁻ CD43⁺ CD11b⁺ CD5⁺ or CD5⁻). Upon activation, B-1 cells downregulate CD11b and CD9 and migrate to the spleen where they upregulate CD6 which is required for B-1 cell proliferation in this compartment. At spleen and in a less extent in the BM, B-1 cells spontaneously differentiate into plasma cells and secret natural IgM

Fig. 3

Homeostatic B-1 cell functions. B-1 cells secrete NAbs that act as first-line defense against invading pathogens and tissue damage by promoting: A complement cascade activation; B pathogen neutralization; C NAbs-dependent phagocytosis of invading pathogens; D opsonization and NAbs-dependent phagocytosis of dead cells; E modulation the immune system by secreting cytokines. PC: phosphorylcholine

Fig. 4

Age-related alterations in B-1 cells and NAbs. The number of B-1 cells in body cavities increases after birth until it peaks in the young adult and is kept until old age. However, tissue specific signals select B-1 cells expressing characteristic BCRs which culminate in the reduction in the diversity of B-1 cells. Although the B-1 cell population is maintained via self-renewal, B-1 cells can be generated de novo by adult BM-derived HSC, which now express TdT. This result in BCRs with more N-additions and more mutations. This, together with reduced hydrophobicity in the CDR-H3 loop, decreases the functionality of NAbs in the elderly, increasing the susceptibility to chronic diseases. The green shades indicate the general age-related alterations. The red shades indicate the age-related alterations in female mice