T cell Tolerance in Early Life

Abstract

T cell-mediated immune tolerance is a state of unresponsiveness of T cells towards specific self or non-self antigens. This is particularly essential during prenatal/neonatal period when T cells are exposed to dramatically changing environment and required to avoid rejection of maternal antigens, limit autoimmune responses, tolerate inert environmental and food antigens and antigens from non-harmful commensal microorganisms, promote maturation of mucosal barrier function, yet mount an appropriate response to pathogenic microorganisms. The cell-intrinsic and cell extrinsic mechanisms promote the generation of prenatal/neonatal T cells with distinct features to meet the complex and dynamic need of tolerance during this period. Reduced exposure or impaired tolerance in early life may have significant impact on allergic or autoimmune diseases in adult life. The uniqueness of conventional and regulatory T cells in human umbilical cord blood (UCB) may also provide certain advantages in UCB transplantation for hematological disorders.

scRNA-seq profiling of neonatal and adult thymus-derived CD4+ T cells by a T cell origin-time tracing model

“…The neonatal immune system performs a bias to immune tolerance ( West, 2016 ; Yang et al., 2020 ). Treg are key regulators in the maintenance of immune tolerance and homeostasis ( Lu et al., 2017 ).…”

“…During the neonatal period, establishing tolerance to self-antigens, food antigens, and microbe antigens is essential to avoid autoimmunity and allergies, and Treg play an important role in this process ( Yang et al., 2020 ). Treg prevent autoimmune diseases and tissue damage caused by misdirected and excessive immune reactions in response to self and foreign targets by secreting immunosuppressive cytokines and engaging in cell surface interactions ( Josefowicz et al., 2012 ).…”

“…Unlike continuous Treg depletion by diphtheria toxin during the neonatal period, two injections of low-dose diphtheria toxin in neonatal Foxp3 DTR mice do not cause severe autoimmunity but lead to dysregulation of subcutaneous tissue in the skin and selective accumulation of Th2 in a unique microanatomical niche ( Boothby et al., 2021 ). Neonatal Treg can be recruited to tissues to suppress immunoreactions ( Yang et al., 2020 ). Treg from the neonatal thymus enter the liver, and depletion of these Treg between Days 7 and 11 leads to Th1-type liver inflammation ( Li et al., 2020 ).…”

Your Regulatory T Cells Are What You Eat: How Diet and Gut Microbiota Affect Regulatory T Cell Development

“…The inability of the adult thymus to generate Padi4-specific tTregs appears to relate to the presentation of the Padi4 peptide by non-mTEC APCs instead of mTECs, which promotes instead clonal deletion. mTECs are the major tTreg inducer in the neonatal thymus, as other APCs (such as pDC and conventional DC) do not efficiently seed the thymus until later in life ( 35 ). Other cells maintain the same function throughout life, such as colonic-derived pDCs.…”

Novel approaches to the treatment of type 1 diabetes

“…Serologic markers such as antibodies to islet cells and glutamic acid decarboxylase‐65 are typically present prior to clinical presentation of disease and lend themselves to measurement, contributing to T1D by presenting islet antigens, including insulin, leading to activation of T cells causing autoimmune destruction of pancreatic beta cells. 3 These islet antigens are expressed in the thymus during development, normally promoting development of T cell‐mediated immune tolerance 4 ; most β‐cell destruction is mediated by autoreactive T‐cells. Most approaches to preventing T1D have been directed at modulation of the autoimmune response.…”