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The Magnitude of CD4⁺ T Cell Recall Responses Is Controlled by the Duration of the Secondary Stimulus¹

Department of Pathology, University of Utah, Salt Lake City, UT 84112

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health (K22AI071112) and the Department of Pathology at the University of Utah.

² Address correspondence and reprint requests to Dr. Matthew A. Williams, Department of Pathology, University of Utah, 15 North Medical Drive East, Salt Lake City, UT 84112. E-mail address: matthew.williams{at}path.utah.edu

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; Lm, Listeria monocytogenes; Lm-OVA, Lm-expressing secreted OVA; DC, dendritic cell; LLO, listeriolysin O.