Divergent T follicular helper cell requirement for IgA and IgE production to peanut during allergic sensitization

Abstract

Immunoglobulin A (IgA) is the dominant antibody isotype in the gut and has been shown to regulate microbiota. Mucosal IgA is also widely believed to prevent food allergens from penetrating the gut lining. Even though recent work has elucidated how bacteria-reactive IgA is induced, little is known about how IgA to food antigens is regulated. Although IgA is presumed to be induced in a healthy gut at steady state via dietary exposure, our data do not support this premise. We found that daily food exposure only induced low-level, cross-reactive IgA in a minority of mice. In contrast, induction of significant levels of peanut-specific IgA strictly required a mucosal adjuvant. Although induction of peanut-specific IgA required T cells and CD40L, it was T follicular helper (TFH) cell, germinal center, and T follicular regulatory (TFR) cell–independent. In contrast, IgG1 and IgE production to peanut required TFH cells. These data suggest an alternative paradigm in which the cellular mechanism of IgA production to food antigens is distinct from IgE and IgG1. We developed an equivalent assay to study this process in stool samples from healthy, nonallergic humans, which revealed substantial levels of peanut-specific IgA that were stable over time. Similar to mice, patients with loss of CD40L function had impaired titers of gut peanut-specific IgA. This work challenges two widely believed but untested paradigms about antibody production to dietary antigens: (i) the steady state/tolerogenic response to food antigens includes IgA production and (ii) TFH cells drive food-specific gut IgA.

B cells and the microbiota: a missing connection in food allergy

“…cholera toxin) and help from CD4 + T cells, which does not include Tfh cells or T-follicular regulatory cells. 52 As deficiency of IgA is associated with increased prevalence of atopic disease, 53,54 these findings suggest that intestinal IgA may protect against allergic inflammation.…”

“…Food-specific IgA has been detected at elevated levels in the serum of infants that become allergic later in life, 55 as well as in mice that have been sensitized to peanut plus a mucosal adjuvant. 52 Yet, others have shown that egg white-specific IgA2 is lower in the serum of allergic children than healthy controls, and only children that recover from the allergy show increased egg white-specific IgA2 over time. 56 Furthermore, consumption of an antigen-free diet results in the reduction of both serum IgA and the frequency of food antigen-specific Tregs in the small intestine that are important for driving oral tolerance.…”

“…[114][115][116] IgG1 serves as an additional marker of the allergic response, and food antigenspecific IgG1 and IgE often show similar expression patterns in mouse models of allergy. 41,52,93 IgG1 has been measured in the saliva of children with allergies 117 and the serum of adults who experience anaphylaxis but do not exhibit increased IgE, 115 demonstrating that IgG1 may be critical to non-IgE-mediated allergy. Though it may play a more minor role compared to IgE, IgG1 can contribute to inflammatory responses that are induced by allergens.…”

Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

“…2,9,96,[101][102][103][104] Indeed, Tfh subpopulations have been described both in humans and mice, and these may play distinct roles in mediating humoral responses in allergy and asthma and lead to specific protection following vaccination and infection. 94,102,105,106 In a key study, Eisenbarth and colleagues demonstrated that IL-13-producing Tfh (Tfh13) cells co-express Bcl6 and GATA3 in mice and humans with IgE antibodies against allergens. Tfh13 cells triggered the production of high-affinity IgE, which led to the induction of anaphylaxis.…”

“…10,108 This likely acts to maintain identity and function or to generate plasticity between CD4 + effector populations and may mediate the functional heterogeneity within Tfh and Th1 populations throughout infection and disease. 102,105,107 Thus, the integration of and balance between transcription factor instruction with inflammatory mediator signaling is of undeniable interest.…”