Human Vγ9Vδ2-T Cells Synergize CD4+ T Follicular Helper Cells to Produce Influenza Virus-Specific Antibody

Abstract

Human Vγ9Vδ2-T cells recognize nonpeptidic antigens and exert effector functions against microorganisms and tumors, but little is known about their roles in humoral immune response against influenza virus infection. Herein, in the coculture of autologous human B cells, dendritic cells and/or naïve CD4 T cells, and Vγ9Vδ2-T cells, we demonstrated that Vγ9Vδ2-T cells could facilitate H9N2 influenza virus-specific IgG and IgM productions in a CD4 T cell-dependent manner. Vγ9Vδ2-T cells promoted the differentiation of CXCR5+PD1+CD4+ T follicular helper (Tfh) cells, CD19+IgD−CD38++ plasma cells (PCs), and drove B cell proliferation as well as immunoglobulin class switching. Interestingly, Vγ9Vδ2-T cells acquired Tfh-associated molecules such as CXCR5, PD1, CD40L, and ICOS during influenza virus stimulation, especially in the presence of CD4 T cells. Moreover, Vγ9Vδ2-T cells promoted CD4 T cells to secrete IL-13 and IL-21, and neutralizing IL-13 and IL-21 significantly reduced the number of CD19+IgD−CD38++ PCs. Using humanized mice, we further demonstrated that Vγ9Vδ2-T cells could synergize CD4 T cells to produce influenza virus-specific antibody. Our findings provide a greater scope for Vγ9Vδ2-T cells in adaptive immunity, especially for the Tfh development and humoral immune responses against influenza virus infection.

γδ T Cells in Antimalarial Immunity: New Insights Into Their Diverse Functions in Protection and Tolerance

“…Interestingly, γδ T cell expression of CD16, which is known to mediate antibody-dependent cellular cytotoxicity (ADCC) in CMV infection ( 24 ) is increased in children in malaria-endemic regions ( 34 , 35 ), suggesting a potential role for γδ T cells in inciting antibody-mediated parasite killing (Figure 1 ). Finally, paralleling previous observations during influenza infection ( 98 ), recent work in the P. berghei mouse model demonstrated a role for γδ T cells in increasing levels of antigen-specific antibodies, Tfh cells, and germinal center B cells via expression of IL-21 and IFNγ early in infection ( 54 ). Altogether, evidence suggests that malaria-responsive γδ T cells are able to use diverse direct and indirect (via recruitment of monocytes, dendritic cells, and CD4+ cells) mechanisms to influence effector responses later in infection.…”

“…In addition, inflammation during recurrent malaria leads to suppression of functional memory B cells (MBC) ( 111 ) and expansion of “inferior” T follicular helper (Tfh) cells ( 112 , 113 ) and “atypical” MBC exhibiting impaired proliferation, cytokine production and antibody secretion ( 114 ). Considering the overlapping timing of immunoregulatory phenotypes developing in γδ T cells and adaptive cells, as well as evidence for γδ T cells impacting germinal center reactions in murine malaria ( 54 ) and Tfh differentiation during influenza ( 98 ), future research should examine the impact of altered γδ T cell function on expansion of MBC and Tfh subsets and interactions with other immune cells.…”

γδ T cells modulate humoral immunity against Plasmodium berghei infection

“…37 This study showed that human cd T cells promote Tfh-cell differentiation, resulting in the induction of plasma cell differentiation and B-cell immunoglobulin class switching. 37 This study showed that human cd T cells promote Tfh-cell differentiation, resulting in the induction of plasma cell differentiation and B-cell immunoglobulin class switching.…”

“…A recent study reported that human Vc9 + Vd2 + cd T cells, a major cd T-cell subset in humans, facilitated H9N2 influenza virus-specific IgG production. 37 This study showed that human cd T cells promote Tfh-cell differentiation, resulting in the induction of plasma cell differentiation and B-cell immunoglobulin class switching. Moreover, they observed that human cd T cells induced CD4 T cells to produce IL-21 and IL-13, resulting in enhanced plasma cell differentiation.…”

Emerging role of γδ T cells in vaccine‐mediated protection from infectious diseases

“…79 Phosphoantigenactivated cells also have non-cytolytic activities in response to pandemic H1N1, producing IFNc and expressing inflammatory chemokines. 80 Relatedly, it was also recently shown that Vc9Vd2 T cells can promote CD4 + T follicular helper cell differentiation, B-cell class switching and influenza virus-specific antibody production in an in vitro co-culture assay, 81 suggesting that these cells may provide both a direct cytotoxic and potential synergistic role in the adaptive immune response to influenza.…”