Avidity maturation of memory CD8 T cells is limited by self-antigen expression

Immune tolerance to self-antigens is a complex process that utilizes multiple mechanisms working in concert to maintain homeostasis and prevent autoimmunity. We developed a system that revealed a population of self-specific CD8 T cells within the endogenous T cell repertoire. Immunization of ovalbumin (OVA)-expressing transgenic mice with recombinant viruses expressing OVA-peptide variants induced self-reactive T cells in vivo that matured into memory T cells able to respond to secondary infection. However, whereas the avidity of memory cells in normal mice increased dramatically with repeated immunizations, avidity maturation was limited for self-specific CD8 T cells. Despite decreased avidity, such memory cells afforded protection against infection, but did not induce overt autoimmunity. Further, up-regulation of self-antigen expression in dendritic cells using an inducible system promoted programmed death-1 expression, but not clonal expansion of preexisting memory cells. Thus, the self-reactive T cell repertoire is controlled by overlapping mechanisms influenced by antigen dose

IgG transmitted from allergic mothers decreases allergic sensitization in breastfed offspring

<p>Abstract</p> <p>Background</p> <p>The mechanism(s) responsible for the reduced risk of allergic disease in breastfed infants are not fully understood. Using an established murine model of asthma, we demonstrated previously that resistance to allergic airway disease transmitted from allergic mothers to breastfed offspring requires maternal B cell-derived factors.</p> <p>Objective</p> <p>The aim of this study was to investigate the role of offspring neonatal Fc receptor for IgG uptake by intestinal epithelial cells (FcRn) in this breast milk transferred protection from allergy.</p> <p>Methods</p> <p>Allergic airway disease was induced during pregnancy in C57BL/6 female mice. These allergic mothers foster nursed naive FcRn^+/-or FcRn^-/-progeny born to FcRn^+/-females that were mated to C57BL/6J-FcRn^-/-male mice. In offspring deficient in FcRn, we expected reduced levels of systemic allergen-specific IgG₁, a consequence of decreased absorption of maternal IgG from the lumen of the neonatal gastrointestinal tract. Using this model, we were able to investigate how breast milk IgG affected offspring responses to allergic sensitization.</p> <p>Results</p> <p>Levels of maternal antibodies absorbed from the breast milk of allergic foster mothers were determined in weanling FcRn-sufficient or -deficient mice. Maternal transmission of allergen-specific IgG₁to breastfed FcRn^-/-offspring was at levels 10³-10⁴lower than observed in FcRn^+/-or FcRn^+/+mice. Five weeks after weaning, when offspring were 8 wk old, mice were sensitized and challenged to evaluate their susceptibility to develop allergic airway disease. Protection, indicated by reduced parameters of disease (allergen-specific IgE in serum, eosinophilic inflammation in the airways and lung) were evident in FcRn-sufficient mice nursed as neonates by allergic mothers. In contrast, FcRn-deficient mice breastfed by the same mothers acquired limited, if any, protection from development of allergen-specific IgE and associated pathology.</p> <p>Conclusions</p> <p>FcRn expression was a major factor in determining how breastfed offspring of allergic mothers acquired levels of systemic allergen-specific IgG₁sufficient to inhibit allergic sensitization in this model.</p

Maternal Transmission of Resistance to Development of Allergic Airway Disease

Parental phenotype is known to influence the inheritance of atopic diseases, such as allergic asthma, with a maternal history being a more significant risk factor for progeny than paternal history. We hypothesized that recall Th1- or Th2-type immune responses during pregnancy would result in transfer of maternal factors that would differentially impact development of immune responsiveness in offspring. Following weaning, susceptibility and severity of allergic airway disease (a murine model of human asthma) was evaluated in progeny, disease being elicited by immunization with OVA-Al(OH)3 and challenge with aerosolized OVA. We found that progeny of mothers with Th1-biased immunity to OVA subjected to recall aerosol challenge during pregnancy had reduced levels of Ag-specific IgE and airway eosinophilia compared with progeny of mothers with Th2-biased immunity to OVA or naive mothers. Interestingly, progeny of mothers with Th1-type immunity to a heterologous albumin, BSA, were not protected from developing OVA-induced allergic airway disease. These findings demonstrated that maternal transfer of protection from development of allergic airway disease to offspring in this model of maternal Th1-type immunity was Ag specific

Distinct Mechanisms Mediate Naïve and memory CD8 T-cell tolerance

Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific population waned, resulting in development of a self-specific memory subset that recalled to subsequent challenge. In striking contrast to naïve CD8 T cells, preexisting antigen-specific memory CD8 T cells failed to expand after antigen induction and essentially ignored the antigen despite widespread expression by dendritic cells. The inclusion of inflammatory signals partially overcame memory CD8 T-cell ignorance of self-antigen. Thus, peripheral CD8 T-cell tolerance for naïve CD8 T cells depended on the continuous presence of antigen, whereas memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation

Dynamics of blood-borne CD8 memory T cell migration in vivo

has been difficult to ascertain the migration patterns of memory T cells in vivo. It has been suggested that memory cells are preferentially retained at the original site of infection to provide continual immunosurveillance, although definitive proof of this concept is lacking. This theory suggests that subsets of memory T cells may exhibit tissue-specific migration patterns (Butcher et al., 1999; Kunkel and Butcher, 2002). In fact, populations of memory cells with differential expression of homing molecules exist (Butcher and Picker, 1996; Campbell and Butcher, 2000). For example, subsets of human peripheral blood memory-phenotype CD4 T cells can be distinguished by the expression of either the �4�7 integrin or the cutaneous lymphocyte antigen (CLA), and this expression pattern also correlates with the appropriat