Although interleukin-2 (IL-2) was initially characterized as the primary T-cell growth factor following in vitro activation1, less is known about its role in shaping T-cell responses to acute infections in vivo. The use of IL-2- or IL-2-receptor-deficient mice is problematic owing to their early development of autoimmunity2,3,4,5, attributable to the central role of IL-2 in the generation, maintenance and function of CD4+CD25+ regulatory T cells6,7,8,9. To bypass these inherent difficulties, we have studied the effect of IL-2 on T-cell responses to acute infections by adopting a mixed chimaera strategy in which T cells lacking the high-affinity IL-2 receptor could be studied in an otherwise healthy mouse containing a full complement of regulatory T cells. Here we show that although IL-2 signalling to pathogen-specific CD8+ T cells affects the number of developing effector and memory cells very little, it is required for the generation of robust secondary responses. This is not due to an altered T-cell-receptor repertoire development or selection, and does not reflect an acute requirement for IL-2 during secondary activation and expansion. Rather, we demonstrate a previously unappreciated role for IL-2 during primary infection in programming the development of CD8+ memory T cells capable of full secondary expansion. These results have important implications for the development of vaccination or immunotherapeutic strategies aimed at boosting memory T-cell function.
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We thank B. Dere and X. Pan for technical assistance in the breeding, maintaining and typing of mouse colonies. The Howard Hughes Medical Institute and grants from the National Institutes of Health supported this work.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
This file contains Supplementary Figures 1–8. The figures display 1) a schematic for our strategy for analysing immune responses by IL-2Rα-deficient T cells in TR-sufficient hosts, 2–3) two separate immunization strategies showing that both LCMV- and Listeria monocytogenes-primed IL-2Rα-deficient T cells make poor recall responses, 4) a schematic for generating naïve IL-2Rα-deficient P14 cells in a TR-sufficient host, 5) an analysis of responses by wt and IL-2Rα-deficient P14 cells in lymph nodes and liver, 6) an analysis of cytokine production and CD69-up-regulation by IL-2Rα-deficient P14 cells, 7) the tracking of P14 immune responses transferred at endogenous frequencies, and 8) immune responses by chimeras generated using a mixture of IL-2-deficient and wildtype bone marrow. (PDF 3142 kb)
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Williams, M., Tyznik, A. & Bevan, M. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 441, 890–893 (2006). https://doi.org/10.1038/nature04790
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