Identification of Human B-1 Helper T Cells With a Th1-Like Memory Phenotype and High Integrin CD49d Expression

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 CD49d^high 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 CD49d^high CD4⁺ T cells. Here, we showed that human CD49d^high 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, CD49d^high CD4⁺ T cells were more abundant in the PEC and showed a higher tendency to form conjugates with B cells than CD49d^low CD4⁺ T cells. Moreover, CD49d^high 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, CD49d^high 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 CD49d^high CD4⁺ T cells. In conclusion, we identified human CD49d^high 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 CD49d^high CD4⁺ T cells are a unique type of B-cell helper T cells distinct from follicular helper T cells.