Interplay of the T Cell Repertoire Development and Early Life Exposure on Incident Risk of Peanut Allergy

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ABSTRACT Peanut allergy (PA) has emerged as a major clinical and public health problem worldwide, due to the dramatic increase in prevalence, its life-long persistence in most cases, and its associated life-threatening anaphylactic response. The causes and precise molecular mechanisms underlying the development of PA remain largely unknown. Available data underscore the early life period (i.e., in-utero and first few years of life) as the critical window in the development of PA, which is also the critical developmental window for the adaptive immune system. There is increasing evidence that T cells play a critical role in modulating tolerance to peanut and risk of PA. Specifically, CD4+ T cells recognize peanut antigens through the engagement of T cell receptors (TCRs). Each individual has a large and highly variable TCR repertoire which is a major determinant in the immune response to a given antigen. To date, few studies have longitudinally characterized TCR repertoire development and dynamics in relation to PA, especially in the context of early life risk or protective factors of PA such as nutrition and metabolomic alteration and their joint associations with PA development during childhood. This proposal, motivated by our intriguing previous work and promising preliminary data, will harness the cutting-edge Adaptive immunoSEQ® technology to deep sequence the TCR ß-chain (TCRß) complementarity determining region 3 (CDR3) at birth (reflecting in-utero development) and at age 1-2 years (reflecting postnatal development) in 300 children (150 peanut allergic and 150 non-allergic, non-sensitized children) from the prospective Boston Birth Cohort (BBC), a NIH-funded U.S. urban, low-resourced underrepresented multi-ethnic cohort. By leveraging the BBC’s existing biospecimen, genome-wide genotype data, metabolome, and extensive epidemiological and clinical databases, we aim to investigate: (1) Longitudinal associations of early life TCRß repertoire development with child risk of PA. We hypothesize that TCRß repertoire features (i.e., composition, diversity, and dynamics) at birth, at age 1-2 years, and their longitudinal changes are associated with childhood risk of PA. We will further identify peanut- specific CD4+ T cell subsets with enriched peanut-specific CDR3 (ps-CDR3) sequences or motifs; (2) The interplay of early life factors, metabolome, and TCRß repertoire on child risk of PA. We hypothesize that early life nutritional and metabolic factors may influence TCRß repertoire development, and, in turn, may jointly affect child risk of PA. This proposal is strengthened by its prospective birth cohort design; a strong multi-disciplinary collaborative team, novel integration of TCRß repertoires with early life exposure to nutrition and metabolome; and focus on underrepresented, under-studied, high risk, predominantly minority children. Successful completion of this project will identify novel biomarkers for early risk assessment of PA and new targets for intervention during the earliest developmental windows. In short, this study represents a unique opportunity to advance the field and open doors to promising new directions to unlock the mystery of PA.