Maternal IgG impairs the maturation of offspring intrathymic IL‐17‐producing γδT cells: Implications for murine and human allergies

Abstract

Background The precise mechanism involved in the acquisition of the IL‐17+ profile of γδT cells, the ligands responsible for this change, and whether this default is acquired during intrathymic maturation need to be elucidated. Objective This study aimed to evaluate whether IL‐17‐producing γδT cells are present in the airways of tolerant offspring from allergen‐sensitized mothers and the possible implication of maternal IgG in the generation of these cells. Methods Female mice were immunized or not, and the allergic response, frequency of γδT cell subsets and cytokine production of the offspring were analysed by flow cytometry. The effects of passive in vivo transfer of purified IgG were investigated in offspring. A translational approach was employed to analyse γδT cells in the thymus and PBMCs from humans. Results Maternal immunization reduced the frequency of spontaneous IL‐17‐producing γδT cells in the thymus, spleen and lung of offspring. This effect was mimicked by the in vivo treatment of females with purified IgG. IgG directly interacted with γδT cell membranes. The modulatory effect of human IgG on human infant intrathymic and adult peripheral γδT cells showed similarities to murine γδT cells, which is rarely reported in the literature. Conclusions & Clinical Relevance Together, our results reveal that IgG from potentially tolerant atopic mothers can influence offspring thymic IL‐17‐producing γδT cell maturation. Furthermore, we suggest that IgG is an unprecedented modulatory factor of murine and human γδT cells. These observations may support the future development of IgG‐based immunoregulatory therapeutic strategies.

The Potential of IgG to Induce Murine and Human Thymic Maturation of IL-10+ B Cells (B10) Revealed in a Pilot Study

“…Next, we performed an in vivo experiment in which both purified IgG pools were passively transferred to females during pregnancy at a dose that was determined based on previous experiments by our group [ 26 , 28 ]. This experiment revealed that the passive transfer of OVA-IgG induced a higher frequency of total B cells (including ProB, PreB, and MatB cells) expressing CD1d at a high intensity but a reduced frequency of mature B10 cells (CD5 + IL-10 + CD1d high ) in the offspring thymus ( Figure 4 A).…”

“…Extensive literature evidence demonstrates that the immune status of IgG donors may be related to differential modulation of thymic lymphocytes [ 26 , 31 , 45 , 46 ], which has been discussed in the literature since 2014 [ 6 , 47 ]. Among related observations, nonatopic IgG may be related to thymic maturation of lymphocytes with an allergy inhibition-related cytokine profile induced by γδT cells [ 48 ] as well as T CD4+ and CD8+ cells [ 5 ].…”

“…A standard curve was constructed to calculate the levels of each IgG subclass (Pharmingen, San Diego, CA, USA). Total human IgG subclasses were measured according to the specifications of the BINDARID Radial Immunodiffusion Kit (RID—Binding Site, Birmingham, UK) as previously described [ 26 ]. Ring diameters were measured, and the concentrations were determined using a reference table provided in the kit.…”

“…Normal female mice were subjected to passive prenatal transfer of Alum-immunized or Alum/OVA-immunized purified IgG as previously standardized by our group [ 26 , 28 ]. Females intravenously received 400 μg of purified IgG (totaling 1600 μg) at 10, 13, 17, and 20 days of gestation.…”

IgG from atopic dermatitis patients induces non‐atopic infant thymic invariant natural killer T (iNKT) cells to produce IL‐4, IL‐17, and IL‐10

“…Our group had been discussing and demonstrating that IgG antibodies can exert a pivotal role mediating the modulation of lymphocytes cytokine production . In this context, we also demonstrated that IgG purified from atopic dermatitis (AD) patients can favor the production of IL‐17 and IL‐10 by thymic TCD4 and TCD8 cells .…”