ABSTRACT
Exposure to inhaled allergens generates T helper 2 (Th2) CD4(+) T cells that contribute to episodes of inflammation associated with asthma. Little is known about allergen-specific Th2 memory cells and their contribution to airway inflammation. We generated reagents to understand how endogenous CD4(+) T cells specific for a house dust mite (HDM) allergen form and function. After allergen exposure, HDM-specific memory cells persisted as central memory cells in the lymphoid organs and tissue-resident memory cells in the lung. Experimental blockade of lymphocyte migration demonstrated that lung-resident cells were sufficient to induce airway hyper-responsiveness, which depended upon CD4(+) T cells. Investigation into the differentiation of pathogenic Trm cells revealed that interleukin-2 (IL-2) signaling was required for residency and directed a program of tissue homing migrational cues. These studies thus identify IL-2-dependent resident Th2 memory cells as drivers of lung allergic responses.
Subject(s)
Asthma/immunology , Immunologic Memory/immunology , Interleukin-2/immunology , Lung/immunology , Th2 Cells/immunology , Allergens/immunology , Animals , Antigens, Dermatophagoides/immunology , Cell Differentiation/immunology , Cell Separation , Disease Models, Animal , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pyroglyphidae/immunologyABSTRACT
Immune responses can make protein therapeutics ineffective or even dangerous. We describe a general computational protein design method for reducing immunogenicity by eliminating known and predicted T-cell epitopes and maximizing the content of human peptide sequences without disrupting protein structure and function. We show that the method recapitulates previous experimental results on immunogenicity reduction, and we use it to disrupt T-cell epitopes in GFP and Pseudomonas exotoxin A without disrupting function.
Subject(s)
Epitopes, T-Lymphocyte/immunology , Immunotoxins/immunology , Protein Engineering/methods , Proteins/immunology , ADP Ribose Transferases/chemistry , ADP Ribose Transferases/genetics , ADP Ribose Transferases/immunology , Animals , Bacterial Toxins/chemistry , Bacterial Toxins/genetics , Bacterial Toxins/immunology , Cell Line, Tumor , Computer-Aided Design , Epitopes, T-Lymphocyte/genetics , Exotoxins/chemistry , Exotoxins/genetics , Exotoxins/immunology , Flow Cytometry , Green Fluorescent Proteins/chemistry , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/immunology , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Immunization , Immunotoxins/chemistry , Immunotoxins/genetics , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Sequence Data , Protein Structure, Tertiary , Proteins/chemistry , Proteins/genetics , Sequence Homology, Amino Acid , Spectrometry, Fluorescence , Support Vector Machine , Virulence Factors/chemistry , Virulence Factors/genetics , Virulence Factors/immunology , Pseudomonas aeruginosa Exotoxin AABSTRACT
PURPOSE: To identify barriers to follow-up eye care in children who failed a visual acuity screening conducted by their primary care provider. METHODS: Children aged 3-14 years who failed a visual acuity screening were identified. A phone survey with the parent of every child was conducted 4 months after the screening. Family demographics, parental awareness of childhood eye diseases and eye care for children, and barriers to follow-up eye care were assessed. RESULTS: Of 971 children sampled, 199 (20.5%) failed a visual acuity screening. The survey was completed by the parents of 58 children (29.1%), of whom 27 (46.6%) presented for follow-up examination. The most common reason for failure to follow-up was parental unawareness of screening results (29.3%). Follow-up rates were higher in children with previous eye examinations than in those without (81% versus 17%; P = 0.005) and in children who waited <2 months for a follow-up appointment than in those who had to wait longer (100% versus 63%; P = 0.024). Child's sex, ethnicity, and health insurance status, parent's marital, education and employment status, household income, and transportation access were not associated with statistically significant different follow-up rates. CONCLUSIONS: Parental unawareness of a failed visual acuity screening is an important barrier to obtaining follow-up. Strategies to improve follow-up rates after a failed visual acuity screening may include communicating the results clearly and consistently, providing education about the importance of timely follow-up, and offering logistic support for accessing eye appointments to families.
