Date Published: September 12, 2013
Publisher: Public Library of Science
Author(s): Brian D. Rudd, Vanessa Venturi, Norah L. Smith, Kito Nzingha, Emily L. Goldberg, Gang Li, Janko Nikolich-Zugich, Miles P. Davenport, Stephen C. Jameson.
Microbial infection during various stages of human development produces widely different clinical outcomes, yet the links between age-related changes in the immune compartment and functional immunity remain unclear. The ability of the immune system to respond to specific antigens and mediate protection in early life is closely correlated with the level of diversification of lymphocyte antigen receptors. We have previously shown that the neonatal primary CD8+ T cell response to replication competent virus is significantly constricted compared to the adult response. In the present study, we have analyzed the subsequent formation of neonatal memory CD8+ T cells and their response to secondary infectious challenge. In particular, we asked whether the less diverse CD8+ T cell clonotypes that are elicited by neonatal vaccination with replication competent virus are ‘locked-in’ to the adult memory T cell, and thus may compromise the strength of adult immunity. Here we report that neonatal memory CD8+ T cells mediate poor recall responses compared to adults and are comprised of a repertoire of lower avidity T cells. During a later infectious challenge the neonatal memory CD8+ T cells compete poorly with the fully diverse repertoire of naïve adult CD8+ T cells and are outgrown by the adult primary response. This has important implications for the timing of vaccination in early life.
The immune system of neonates is generally characterized as immature and more susceptible to infections with various pathogens –. Many of the most debilitating infections are inflicted by intracellular pathogens that are either vertically transmitted or acquired very early on in life (e.g. HIV, CMV, EBV, TB, HSV). Although CD8+ T cells are considered the key players in combating these intracellular pathogens, their capacity to provide protective immunity in neonates is still poorly understood. Importantly, since the timing of infection in some cases affects the subsequent pathogen load and pathogenesis of infection, we wished to understand whether early exposure to infection or vaccination compromises the later ability to control infection as an adult.
The focus of this report was to determine how the composition and responsiveness of the memory CD8+ T cell pool is altered by neonatal vaccination or infection that occurs prior to the diversification of the CD8+ T cell repertoire. Our results demonstrate that the restricted neonatal T cell memory pool induced by early vaccination is in fact comprised of fewer clonotypes that are also of lower avidity than the adult response. However, while vaccination early in life recruits many of these ‘less fit’ clonotypes and allows them to persist in the memory CD8+ T cell compartment, these neonatal memory clonotypes are not efficiently recruited into the proliferative recall response to secondary challenge. In the absence of a strong neonatal memory response mediating early viral control, a robust adult primary response is generated, which ultimately comes to dominate the neonatal memory population. Despite this contribution from the adult repertoire, the secondary response in mice vaccinated as neonates remained significantly restricted, in terms of the diversity of TCR clonotypes, compared with secondary responses in adult-vaccinated mice. These observations describe a situation that is mechanistically similar to the phenomenon of ‘original antigenic sin’, in which prior infections with a related pathogen can “trap” the immune system into responding with less efficient memory clonotypes. However, in this case, the same pathogen may “trap” less efficient clonotypes into the immune reserve simply by priming these T cells during the early stages of development.