Neonatal tolerance represents an immune response that lacks Th1 cells but displays an indubitable bias towards Th2. This provides an environmental pre-disposition to allergies and infections. Recently, we developed a neonate-to-neonate T cell receptor (TCR) transgenic transfer model that tracks T cells in vivo and overcomes the limitations associated with the neonatal system. We then used this model to investigate the mechanism(s) underlying the lack of Th1 and excess of Th2 cells in the response of the newborn. The findings indicated that both Th1 and Th2 cells develop upon priming with antigen on the day of birth. However, rechallenge with antigen yields secondary responses in which the Th2 cells respond and produce IL-4 but the Th1 cells up-regulate IL-13R?1 and undergo apoptosis. Moreover, we found that IL-13R?1 associates with IL- 4R? to form an IL-4R?/ IL-13R?1 heteroreceptor that IL-4 from Th2 cells uses to drive apoptosis of Th1 lymphocytes. Further analysis indicated that when adult T cells are transferred into one-day-old Balb/c mice and primed with antigen within this neonatal environment they do not up-regulate IL-13R?1 chain or undergo apoptosis. Instead, the adult T cells develop both primary and secondary Th1 response. Given that IL-4R1 is constitutively expressed on Th1 cells but IL-13R?1 can be induced only during the neonatal stage and Th2- biased neonatal immunity develops in both Th1- and Th2 prone mice we postulate that IL-13R?1 expression is under developmental regulation that controls the formation of IL-4R1/IL-13R?1 heteroreceptor which mediates the Th2 bias of neonatal immunity in both Th1- and Th2-prone mice. To address this hypothesis we propose to generate an IL-13R?1-GFP knock-in mouse to further overcome the limitations associated with the newborn and utilize this tool to determine whether IL-13R?1 expression is subject to developmental regulation at the fetal and neonatal stages. Also, we will utilize the IL-13R?1-GFP mice to determine whether IL-13R?1 up- regulation on neonatal Th1 cells occurs in Th1-prone C57BL/6 mice and allows for the formation of IL-4R?/IL- 13R?1 heteroreceptor to be utilized by IL-4 to drive apoptosis of Th1 cells leading to Th2 biased neonatal immunity.

Public Health Relevance

More than 5 decades ago 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 this 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 reactions, graft rejection and transplantation tolerance. However, recent advances in this field indicated that immunity develops in the neonate but the responses lack Th1 cells and manifest an indubitable bias towards Th2 cells. This unbalanced response likely sustains susceptibility to microbial infections and allergic reactions. 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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD060089-01A2
Application #
7749204
Study Section
Special Emphasis Panel (ZRG1-IMM-H (03))
Program Officer
Coulombe, James N
Project Start
2009-09-18
Project End
2011-08-31
Budget Start
2009-09-18
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$176,096
Indirect Cost
Name
University of Missouri-Columbia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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
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