γδ T cells modulate humoral immunity against Plasmodium berghei infection

Abstract

It is unclear whether γδ T cells are involved in humoral immunity against Plasmodium infection. Here, we show that B-cell-immunodeficient mice and γδ T-cell-deficient mice were incapable of protecting against Plasmodium berghei XAT parasites. γδ T-cell-deficient mice developed reduced levels of antigen-specific antibodies during the late phase of infection. The numbers of follicular helper T cells and germinal centre B cells in γδ T-cell-deficient mice were lower than in wild-type mice during the late phase of infection. Expression profiling of humoral immunity-related cytokines in γδ T cells showed that interleukin-21 (IL-21) and interferon-γ (IFN-γ) are increased during the early stage of infection. Furthermore, blockade of IL-21 and IFN-γ signalling during the early stage of infection led to reduction in follicular helper T cells and germinal centre B cells. γδ T-cell production of IL-21 and IFN-γ is crucial for the development and maintenance of follicular helper T cells and germinal centre B cells during the late phase of infection. Our data suggest that γδ T cells modulate humoral immunity against Plasmodium 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.…”

Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases

“…Despite the tissue distribution and the omnipresence of IL-21 target cells in tissues in which protozoan and helminth parasites reside, the role of the IL-21/IL-21R signaling pathway in protection against and/or the promotion of inflammation during parasitic infections is not fully understood. In recent years, however, it has been observed that IL-21 is induced in the periphery and mucosal tissues of humans and mice after infection with some parasites (Stumhofer et al, 2013; Carpio et al, 2015; Perez-Mazliah et al, 2015; Cai et al, 2016; Ryg-Cornejo et al, 2016; Moretto et al, 2017; Inoue et al, 2018; Wikenheiser et al, 2018) (Table 1). However, the exact mechanisms by which this signaling pathway regulates host immunity during parasitic infections are still unclear.…”

“…IL-21 is expressed in several murine malaria models, including P. berghei (Ryg-Cornejo et al, 2016; Inoue et al, 2018), Plasmodium chabaudi (Perez-Mazliah et al, 2015; Sebina et al, 2017) and Plasmodium yoelii (Wikenheiser et al, 2018). Genetic disruption of the IL-21/IL-21R singling axis compromised P. chabaudi -specific IgG responses and resulted in the impairment of memory B cell generation.…”

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

“…72 These cells may also be important in modulating functional T follicular helper (Tfh) cell and germinal centre B-cell responses. 74 In contrast to these indirect roles in protection, cd T cells appear to act as important effector cells following vaccination with nonlethal Plasmodium yoelii sporozoites. 75 Results from mice lacking ab T cells further suggest that cd T-cell cytotoxicity may become more effective after interaction with CD4 + T cells.…”