The Magnitude of CD4+ T Cell Recall Responses Is Controlled by the Duration of the Secondary Stimulus

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Abstract
The parameters controlling the generation of robust CD4+ T cell recall responses remain poorly defined. In this study, we compare recall responses by CD4+ and CD8+ memory T cells following rechallenge. Homologous rechallenge of mice immune to either lymphocytic choriomeningitis virus or Listeria monocytogenes results in robust CD8+ T cell recall responses but poor boosting of CD4+ T cell recall responses in the same host. In contrast, heterologous rechallenge with a pathogen sharing only a CD4+ T cell epitope results in robust boosting of CD4+ T cell recall responses. The disparity in CD4+ and CD8+ T cell recall responses cannot be attributed to competition for growth factors or APCs, as robust CD4+ and CD8+ T cell recall responses can be simultaneously induced following rechallenge with peptide-pulsed dendritic cells. Instead, CD4+ T cell recall responses are dependent on the duration of the secondary challenge. Increasing the rechallenge dose results in more potent boosting of CD4+ T cell recall responses and artificially limiting the duration of secondary infection following heterologous rechallenge adversely impacts the magnitude of CD4+ T cell, but not CD8+ T cell, recall responses. These findings suggest that rapid pathogen clearance by secondary CTL following homologous rechallenge prevents optimal boosting of CD4+ T cell responses and therefore have important practical implications in the design of vaccination and boosting strategies aimed at promoting CD4+ T cell-mediated protection.