In 1956 Sir Medawar demonstrated that rodents injected at birth with splenocytes from a genetically different donor were able to accept transplants from that donor as an adult. These landmark experiments suggested that neonatal exposure to antigen leads to tolerance of such antigen during a later encounter. Ever since, the neonatal period was thought of as a window during which T cell tolerance is feasible and the approach has proven useful for understanding allogeneic and allergic reactions, graft rejection and transplantation tolerance. The mechanism underlying neonatal tolerance remains, however, largely undefined. The initial theory on this issue suggested that T cell deletion is the lead mechanism for neonatal tolerance. However, recent advances in this field indicated that immunity develops in the neonate but the responses are biased towards Th2 cells producing IL-4 cytokine and thus do not support the usual IFNy-mediated inflammatory reactions. This application proposes to delineate the mechanism(s) underlying the bias of neonatal immunity towards Th2 cells. A neonate-to-neonate T cell receptor (TCR) transgenic (Tg) T cell transfer system was developed which facilitated analysis of the primary Th1 responses. Preliminary results indicate that one-day old Balb/c mice recipient of one-day-old ovalbumin (OVA)-specific TCR Tg DO11.10 T cells and exposed to OVA develop primary responses comprised of both Th1 and Th2 cells. However, upon re-challenge with OVA at an adult age the Th2 respond but the Th1 undergo apoptosis. We have discovered that IL-4 from the Th2 cells utilizes a heteroreceptor comprising IL-4Ra and IL-13Ra1 chains to drive death of Th1 cells and bias neonatal immunity towards Th2 cells. In this application we propose to determine whether IL-4Ra/ IL- 13Ra1 expression is a common trait of the neonate and drives bias of immunity in different mouse strains and different antigenic systems. Also, we will examine the developmental regulation of the expression of the heteroreceptor. Finally, we propose to delineate the molecular mechanism by which IL-4 drives apoptosis of Th1 cells through the IL-4Ra/ IL-13Ra1 heteroreceptor signaling. Understanding the function of the neonatal immune system could facilitate development of strategies to balance Th1 and Th2 responses and overcome the susceptibility of the neonate to allergic reactions and microbial infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Prabhudas, Mercy R
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University of Missouri-Columbia
Schools of Medicine
United States
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Ellis, Jason S; Guloglu, F Betul; Zaghouani, Habib (2016) Presentation of high antigen-dose by splenic B220(lo) B cells fosters a feedback loop between T helper type 2 memory and antibody isotype switching. Immunology 147:464-75
Dhakal, Mermagya; Miller, Mindy M; Zaghouani, Adam A et al. (2015) Neonatal Basophils Stifle the Function of Early-Life Dendritic Cells To Curtail Th1 Immunity in Newborn Mice. J Immunol 195:507-18
Dhakal, Mermagya; Hardaway, John C; Guloglu, Fatma Betul et al. (2014) IL-13R?1 is a surface marker for M2 macrophages influencing their differentiation and function. Eur J Immunol 44:842-55
Guloglu, F Betul; Ellis, Jason S; Wan, Xiaoxiao et al. (2013) Antigen-free adjuvant assists late effector CD4 T cells to transit to memory in lymphopenic hosts. J Immunol 191:1126-35
Hoeman, Christine M; Dhakal, Mermagya; Zaghouani, Adam A et al. (2013) Developmental expression of IL-12R?2 on murine naive neonatal T cells counters the upregulation of IL-13R?1 on primary Th1 cells and balances immunity in the newborn. J Immunol 190:6155-63
Haymaker, Cara L; Guloglu, F Betul; Cascio, Jason A et al. (2012) Bone marrow-derived IL-13Rýý1-positive thymic progenitors are restricted to the myeloid lineage. J Immunol 188:3208-16
Ellis, Jason S; Guloglu, F Betul; Tartar, Danielle M et al. (2010) APCs expressing high levels of programmed death ligand 2 sustain the development of CD4 T cell memory. J Immunol 185:3149-57
Zaghouani, Habib; Hoeman, Christine M; Adkins, Becky (2009) Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol 30:585-91
Yu, Ping; Haymaker, Cara L; Divekar, Rohit D et al. (2008) Fetal exposure to high-avidity TCR ligand enhances expansion of peripheral T regulatory cells. J Immunol 181:73-80
Lee, Hyun-Hee; Hoeman, Christine M; Hardaway, John C et al. (2008) Delayed maturation of an IL-12-producing dendritic cell subset explains the early Th2 bias in neonatal immunity. J Exp Med 205:2269-80

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