Neonates are particularly vulnerable to intracellular pathogens. The basic mechanisms underlying the generation of poor CD8+ T cell responses in neonates are unknown, making it impossible to develop treatments and vaccines to promote effective CD8+ T cell immunity in early life. Therefore, we developed an animal model of neonatal infection and characterized the generation of primary and memory CD8+ T cells in neonatal and adult mice. Unexpectedly, the preliminary data indicates that neonatal CD8+ T cells may form poor memory, not because of an inability to respond, but rather because they more quickly become terminally differentiated. Thus, the goal of this proposal is to quantify the extent to which cell-intrinsic and environmental differences contribute to impaired neonatal memory CD8+ T cells. Our overall hypothesis is that differences in T cell replication and homeostasis alter the generation and maintenance of memory CD8+ T cells following infection. In the first aim, it will be determined whether memory CD8+ T cell development is altered in early life because na?ve neonatal CD8+ T cells are intrinsically different prior to infection (due o extensive homeostatic proliferation or derivation from different aged hematopoietic stem cells). In the second aim, we will determine how environmental differences (amount of homeostatic cytokines, CD4+ T cell help) influence the generation of neonatal memory CD8+ T cells. Using a basic approach of transferring neonatal and adult CD8+ T cells into neonatal and adult recipient mice prior to infection combined with statistical analysis and modeling of T cell dynamics, we will dissect out the key cell-intrinsic and environmental differences present during every stage of the neonatal CD8+ T cell response (e.g. expansion, contraction, maintenance). In doing so, the most important mechanisms contributing to poor CD8+ T cell immunity as well as the maximum amount of benefit that can be obtained by fixing these defects will be identified. Ultimately, knowledge gained from these studies will provide key insight into how best to improve CD8+ T cell immunity during critical stages of development.
Neonates are highly susceptible to infection and respond poorly to vaccination. Upon completion of this proposal, we expect to have a better mechanistic understanding of these immune impairments, while also offering insight into safe and effective strategies to boost immunity early in life.
|Reynaldi, Arnold; Smith, Norah L; Schlub, Timothy E et al. (2016) Modeling the dynamics of neonatal CD8(+) T-cell responses. Immunol Cell Biol 94:838-848|
|Venturi, Vanessa; Nzingha, Kito; Amos, Timothy G et al. (2016) The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection. J Immunol 196:1604-16|
|Wissink, Erin M; Smith, Norah L; Spektor, Roman et al. (2015) MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells. Genetics 201:1017-30|
|Smith, Norah L; Wissink, Erin M; Grimson, Andrew et al. (2015) miR-150 Regulates Differentiation and Cytolytic Effector Function in CD8+ T cells. Sci Rep 5:16399|
|Smith, Norah L; Wissink, Erin; Wang, Jocelyn et al. (2014) Rapid proliferation and differentiation impairs the development of memory CD8+ T cells in early life. J Immunol 193:177-84|