Research Article: The Timing of Stimulation and IL-2 Signaling Regulate Secondary CD8 T Cell Responses

Date Published: October 2, 2015

Publisher: Public Library of Science

Author(s): Shaniya H. Khan, Matthew D. Martin, Gabriel R. Starbeck-Miller, Hai-Hui Xue, John T. Harty, Vladimir P. Badovinac, Chris A. Benedict.


Memory CD8 T cells provide protection to immune hosts by eliminating pathogen-infected cells during re-infection. While parameters influencing the generation of primary (1°) CD8 T cells are well established, the factors controlling the development of secondary (2°) CD8 T cell responses remain largely unknown. Here, we address the mechanisms involved in the generation and development of 2° memory (M) CD8 T cells. We observed that the time at which 1° M CD8 T cells enter into immune response impacts their fate and differentiation into 2° M CD8 T cells. Late-entry of 1° M CD8 T cells into an immune response (relative to the onset of infection) not only facilitated the expression of transcription factors associated with memory formation in 2° effector CD8 T cells, but also influenced the ability of 2° M CD8 T cells to localize within the lymph nodes, produce IL-2, and undergo Ag-driven proliferation. The timing of stimulation of 1° M CD8 T cells also impacted the duration of expression of the high-affinity IL-2 receptor (CD25) on 2° effector CD8 T cells and their sensitivity to IL-2 signaling. Importantly, by blocking or enhancing IL-2 signaling in developing 2° CD8 T cells, we provide direct evidence for the role of IL-2 in controlling the differentiation of Ag-driven 2° CD8 T cell responses. Thus, our data suggest that the process of 1° M to 2° M CD8 T cell differentiation is not fixed and can be manipulated, a notion with relevance for the design of future prime-boost vaccination approaches.

Partial Text

Memory CD8 T cells are an important component of the adaptive immune response because of their ability to establish long-lasting protective immunity against recurrent infections [1–6]. Memory CD8 T cells are derived from naïve Ag-specific CD8 T cells that responded to pathogen-derived Ags, underwent robust proliferative expansion, and survived the contraction phase [7,8]. The protection afforded by memory CD8 T cells is due to persistence at higher numbers, unique trafficking abilities and localization in peripheral tissues, and rapid initiation of effector functions after Ag re-encounter [1,9,10]. These characteristics of primary memory (1° M) CD8 T cells distinguish them from the naïve CD8 T cells they are derived from.

While the formation of 1° M CD8 T cells has been comprehensively studied, much less is known about the factors influencing the generation of 2° M CD8 T cell responses. Longitudinal analyses of developing 1° M and 2° M CD8 T cells suggests that the rate of acquiring a long-term memory phenotype and function varies substantially between these two populations of cells [2]. Prime-boost protocols are often implemented to increase the overall numbers of memory CD8 T cells, leading to the generation of memory CD8 T cells that have encountered Ag more than once. Therefore, understanding if the factors that impact the differentiation of 1° M CD8 T cells also influence 2° M CD8 T cell responses has implications in the design of future consecutive prime-boost vaccine protocols. Here, we show that during an infection recruitment of pathogen-specific 1° M CD8 T cells is not simultaneous, and timing of entry into an immune response relative to the onset of infection impacts the outcome of the ensuing 2° M CD8 T cell response. Specifically, late-entry of 1° M CD8 T cells into the immune response facilitates accelerated acquisition of 2° M characteristics. We also show that the timing of stimulation of 1° M CD8 T cells differentially regulates IL-2 signaling in differentiating 2° effector CD8 T cells, suggesting that this signaling mechanism contributes to the programming of 2° CD8 T cell responses.




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