Concurrent cross‐reactivity of microbiota‐derived epitopes to both self and pathogens may underlie the “Hygiene hypothesis”

Abstract

The current iteration of the "Hygiene hypothesis" proposes precipitous decline in exposure to conserved microbial products and metabolites in individuals in developed countries undermines innate self-nonself "training" of immune system leading to allergy and autoimmunity. However, lack of innate "training" alone fails to account for the antigen-driven nature of these immunopathologies. Here, we advance an alternative, antigen-specific interpretive framework, SPIRAL (Specific ImmunoRegulatory Algorithm) that predicts "loss" of commensal microbiota-derived epitopes cross-reactive to both self and pathogens, rather than conserved microbial moieties or metabolites, underlies the "Hygiene hypothesis." By mechanistically delineating how loss of selective microbiota in predisposed individuals could lead to corresponding "holes" in the epitope-specific Foxp3 regulatory T cell repertoire and subsequent selective immunopathologies, SPIRAL represents a novel interpretation of cross-reactivity that could enable targeted discovery of microbiota species and their associated Treg epitopes "missing" in the diseases "Hygiene hypothesis" implicates, and provides a roadmap for a novel unified interpretation of self-nonself discrimination and T helper phenotype selection.

Shared TCR epitope cross-reactivity could permit dyads of Foxp3+ regulatory and IL-2-producing T cell precursors to escape thymic purge

“…We previously introduced a novel framework dubbed SPIRAL (Specific ImmunoRegulatory Algorithm) which suggests that antigen cross-reactivity of TCRs expressed by thymic Tregs could provide a mechanistic basis for their broad functionality (Usharauli and Kamala, 2018). SPIRAL predicts that generation of thymus-derived epitope-specific Tregs and their maintenance in the periphery requires their persistent engagement with crossreactive MHC class II/epitope complexes presented sequentially, first in the thymus to select them and later derived from endogenous microbiota in the periphery to maintain them (Delpoux et al, 2012).…”

“…Since SPIRAL mandates antigen-specific inhibition of ineffective T cell responses by Tregs (Usharauli and Kamala, 2018;Pohar et al, 2018;Akkaya et al, 2019), their sensing of IL-2 as a proxy for such ineffective T cell responses must be antigen-specific as well (Setoguchi et al, 2005;Almeida et al, 2006;Amado et al, 2013;Liu et al, 2015). In other words, Tregs cannot just sense IL-2 produced by random T cells but instead must share antigen-specificity in the form of crossreactivity with such IL-2 producing T cells (Wolf et al, 2016).…”

“…We previously proposed that peripheral maintenance of thymic Foxp3+ Tregs requires the presence of specific microbiota species that supply epitopes crossreactive to those the thymus presents to select such Tregs in the first place (Pacholczyk et al, 2007;Malchow et al, 2013;Al Nabhani et al, 2019). We propose that disruption of this antigen-specific relationship between microbiota and thymic Tregs rather than lack of 'innate' training is the natural basis for specific allergies, autoimmune diseases and other inflammatory disorders under the 'Hygiene hypothesis' (Usharauli and Kamala, 2018).…”

“…Were this not so, there wouldn't even be ineffective T cell responses to nonself epitopes since at least one of out of many heterogeneous T helper cell responses (Th 1 , Th 2 , Th 17 , Th 22 , Th 9 , etc) would be effective. Moreover, both ineffective T helper responses to nonself and their control by thymic Tregs must be epitope-specific (Usharauli and Kamala, 2018;DiToro et al, 2018;Kotov et al, 2019;Akkaya et al, 2019). In contrast, ineffective, polarizing T helpers must cross-inhibit other types of T helper differentiation in an epitope non-specific manner (otherwise, again, there would not be an ineffective T helper response to begin with).…”

“…We previously proposed that both self-nonself discrimination and T helper phenotype selection are one and the same process controlled by epitope-specific thymic Tregs (Usharauli and Kamala, 2018). We initially considered that specific innate signaling intrinsic to some nonself antigens in conjunction with specific TCR signaling intrinsic to epitope-specific T cells could produce such ineffective T helper polarization.…”