Abstract
Human B-1 cells have been proposed to be CD20+CD27+CD43+CD1c− B cells found in the umbilical cord and adult peripheral blood, but their regulatory mechanisms have not been well elucidated. Previously, we reported that mouse CD49dhigh CD4+ T cells could enhance the secretion of natural antibodies by B-1 cells. In this study, we aimed to investigate the presence and helper functions of the human equivalents of murine CD49dhigh CD4+ T cells. Here, we showed that human CD49dhigh CD4+ T cells found in the peritoneal cavity (PEC), spleen, and peripheral blood can enhance the production of IgM antibodies by B-1 cells. As revealed in mouse, CD49dhigh CD4+ T cells were more abundant in the PEC and showed a higher tendency to form conjugates with B cells than CD49dlow CD4+ T cells. Moreover, CD49dhigh CD4+ T cells showed a Th1-like memory phenotype, characterized by high expression of CD44 and CXCR3; low expression of CD62L and CCR7; rapid production of IFN-γ, tumor necrosis factor-α, and IL-2 upon stimulation with phorbol myristate acetate and ionomycin; and rapid proliferation upon stimulation with anti-CD3 and anti-CD28 antibodies. These cells also expressed high levels of PD-1, ICOS, and CD5, suggesting that they are undergoing chronic stimulation. Remarkably, CD49dhigh CD4+ T cells specifically helped B-1 cells, but not follicular memory B cells (CD27+ CD43−CD1c−) or marginal zone B cells (CD27+CD43−CD1c+), produce IgM and IgG antibodies. In parallel, the titer of human anti-blood group A IgM was positively correlated with the frequency of CD49dhigh CD4+ T cells. In conclusion, we identified human CD49dhigh CD4+ T cells with a Th1-like memory phenotype that secrete Th1 proinflammatory cytokines and help B-1 cells secrete antibodies, thereby aiding in primary defense. We suggest that these CD49dhigh CD4+ T cells are a unique type of B-cell helper T cells distinct from follicular helper T cells.
Highlights
B-1 cells comprise a fetal progenitor-derived self-renewing population of B cells that generate natural antibodies as a primary defense against microbial infection [1, 2]
We found that CD49dhigh CD4+ T cells were present in the human peritoneal cavity (PEC), SP, and peripheral blood (PB), and we revealed that they exhibited a Th1-like memory phenotype, similar to those of mouse CD49dhigh CD4+ T cells
Since CD49dhigh CD4+ T cells with a Th1-like memory phenotype and B-1 cell helper activity are enriched in the mouse PEC [8], we first examined the frequency of CD49dhigh CD4+ T cells in the peritoneal fluid of peritoneal dialysis patients, SPs of brain-death patients, and the PB of healthy donors to determine whether CD49dhigh CD4+ T cells with a memory phenotype are abundant in the human PEC
Summary
B-1 cells comprise a fetal progenitor-derived self-renewing population of B cells that generate natural antibodies as a primary defense against microbial infection [1, 2]. Human B-1 Helper T Cells on their fundamental B-1 cell functions, such as spontaneous IgM secretion, efficient T cell stimulation, and tonic B cell receptor-mediated signaling [3]. B-1 cells are known to function in a T cell-independent manner and are usually activated through innate immunity receptors such as TLR4 and TLR9 [4, 5], whereas conventional B-2 cells require help from CD4+ T cells for differentiation into memory B or plasma cells and produce high-affinity antibodies. The active interaction between B-1 and CD4+ T cells may activate reverse signaling for B-1 cell help from CD4+ T cells, as is the case in mouse B-1a cells [8, 9]. It would be interesting to determine whether human CD4+ T cells are able to provide help for human B-1 cells, as well as which kinds of human CD4+ T cells are responsible for this B-1 helper function
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