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CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes


A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T-helper (TH) cells in the priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4+ T cells, others, such as those mediated through ‘cross-priming’ by host antigen-presenting cells, are dependent on TH cells1,2,3,4. A clearer understanding of the contribution of TH cells to CTL development has been hampered by the fact that most TH-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas TH-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of TH-dependent and TH-independent CTLs and find in both cases that CD4+ T cells are dispensable for primary expansion of CD8+ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of TH cells during, but not after, priming. Our results demonstrate that T-cell help is ‘programmed’ into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.

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Figure 1: Functional expansion of T-helper (TH) cell-dependent CD8+ T cells cross-primed in the absence of CD4+ T-cell help.
Figure 2: Primary and secondary cytotoxic responses of TH-dependent cytotoxic T lymphocytes (CTLs).
Figure 3: Defective secondary expansion of CTLs cross-primed in the absence of TH cells.
Figure 4: Defective secondary expansion of TH-independent CD8+ T cells primed in the absence of CD4+ T-cell help.


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This work was supported by grants from the National Institutes of Health, the American Cancer Society, and CaP CURE to S.P.S. The authors thank G. Palioungas for technical assistance and the staff of the LIAI animal facility for animal care.

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Correspondence to Stephen P. Schoenberger.

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Janssen, E., Lemmens, E., Wolfe, T. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003).

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