![]() The data presented here show an association between early life T cell repertoire restriction with respiratory tract infections. This study provides the highest resolution data derived from daily symptom diaries in the first 6 years of life along with standardized questionnaires at defined time points, thereby allowing meaningful correlations of immune repertoire metrics with susceptibility to acute respiratory infections (ARI). Here, we used the unique LoewenKIDS cohort to study peripheral blood adaptive immune repertoires of 120 infants at the age of 12 months along with infection-related metadata 18. Longitudinally monitored cohorts with high-quality and high-resolution information about infectious episodes as well as a standardized sampling of biomaterials are required to study such questions. Even more so, it is unclear if specific repertoire architectures in newborns, infants or children are informative for infection vulnerability. Most of these studies have been performed in adults and there is only scarce knowledge on repertoire configurations in infants or children in general. Many investigations have shown the effects of aging and imprints of autoimmunity, specific infections, or vaccinations on the receptor repertoire over a lifetime 11, 12, 13, 14, 15, 16, 17. The shapes of such receptor repertoires are based on the antigens encountered throughout life, therefore repertoire “snapshots” provide information on the current immune status as well as the antigen history. High throughput adaptive immune receptor repertoire sequencing (AIRR-seq) of B and T cells has opened up avenues for the in-depth characterization of immune architectures in various tissues as well as-most prominently-in the peripheral blood. Thereby, T cells still retain a particular epigenetic program and a more rapid onset of exhaustion in the newborn 9 and B cell responses to some vaccines increase with age at immunization 10. Both the fetal T and B cell repertoire begin to form and diversify as early as at the end of the first trimester of pregnancy 7, 8. In young children, adaptive immunity is not deficient as evidenced by specific responses even to fetal infections 6, but a certain degree of immaturity is evident in early life. While the innate branch of the immune system provides a first and rather unspecific line of defense against pathogens, B and T cells of the adaptive immune system act in a more sophisticated way to control infections by recognizing epitopes with their unique antigen receptor formed through genetic recombination of V, D and J genes. For most children with increased vulnerability to infection and without evident genetic or environmental triggers, we lack insight into the immune configurations that may underlie these phenotypes. Children with primary immunodeficiencies often show unusual infection manifestation, but account only for a small minority of cases 4, 5. daycare or having siblings), as well as genetic traits ranging from polygenic predisposition to primary immunodeficiencies through monogenetic inborn errors of the immune system. in preterm infants), exposure to pathogens through early social interactions (e.g. Different factors may impact the frequency and severity of early life infections: the degree of immune immaturity and integrity of barrier defenses (e.g. The spectrum ranges from sporadic mild diseases such as seasonal acute respiratory infections to severe infections in the immediate postnatal period 3. Newborns, infants and young children are more susceptible to infection than adults 1, 2. Moreover, this study provides a valuable resource of millions of T and B cell receptor sequences from infants with available metadata for researchers in the field. Together, this study supports that-regardless of T cell functionality-the breadth of the T cell repertoire is associated with the number of acute respiratory infections in the first 4 years of life. No correlation of T or B cell repertoire metrics with other parameters such as sex, birth mode, older siblings, pets, the onset of daycare, or duration of breast feeding was noted. Infants with inadequately low T cell repertoire diversity or high clonality showed higher numbers of acute respiratory infections over the first 4 years of life. Low antigen-dependent somatic hypermutation of B cell repertoires, as well as low T and B cell repertoire clonality, high diversity, and high richness especially in public T cell clonotypes reflected the immunological naivety at 12 months of age when high thymic and bone marrow output are associated with relatively few prior antigen encounters. We set out to gain insight into peripheral blood B and T cell repertoires from 120 infants of the LoewenKIDS birth cohort to investigate potential determinants of early life respiratory infections.
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