Neonates are particularly susceptible to infectious diseases. The goal of this proposal is to link various stages of development with diversification of the CD8+ TCR repertoire and immune defense. To accomplish this goal, we will investigate the capacity of antigen-specific neonatal and adult CD8+ T cells to generate appropriate immune responses against acute and persistent infections. Our overall focus is on determining the long-term consequences of acute and persistent infections in neonates by examining to what extent neonatal CD8+ T cell clonotypes are maintained through development and provide immune defense as adults. Our central hypothesis is that infections early in life 'lock-in'a less diverse and structurally distinct CD8+ TCR repertoire that hinders immune defense when challenged later as adults. We predict that early infections allow low avidity fetal/neonatal CD8+ TCR clonotypes to dominate adult memory CD8+ T-cell compartments and will directly correlate with impaired functionality of T cell immunity against acute and chronic persistent infections. This will be tested as follows, with specific aim 1 (SA1) being completed in the mentored phase and specific aim 2 (SA2) performed in the independent phase. SA1: Do acute infections early in life 'lock-in'a less diverse memory CD8+ TCR repertoire that impairs adult CD8+ T cell immunity? This will be examined by immunizing neonatal and adult mice with a live infectious vector and later challenging all mice with HSV-1. SA2: Do persistent infections early in life alter the clonal composition of tissue resident memory cells and their ability to control latency later in life? We will assess the ability of HSV-1 to sequester the neonatal repertoire into the trigeminal ganglia and correlate repertoire diversity with immune surveillance and functionality during latent infection. Knowledge gained from these studies will better inform us on how infections early in life alter the clonal composition of the adult memory T cell pool and provide insight into improving long-lasting T cell immunity during critical stages of early development.
Many acute and persistent viral infections are transmitted early in life and are responsible for long-term morbidity and mortality. At the conclusion of these studies, we expect to have a better mechanistic understanding of these immune impairments, while also offering insight into safe and effective strategies to boost immunity during critical stages of early development.
|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|
|Venturi, Vanessa; Rudd, Brian D; Davenport, Miles P (2013) Specificity, promiscuity, and precursor frequency in immunoreceptors. Curr Opin Immunol 25:639-45|