Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells


The rules that govern memory T cell differentiation are not well understood. This study shows that after antigenic stimulation naïve CD8+ T cells become committed to dividing at least seven times and differentiating into effector and memory cells. Once the parental naïve CD8+ T cell had been activated, this developmental process could not be interrupted and the daughter cells continued to divide and differentiate in the absence of further antigenic stimulation. These data indicate that initial antigen encounter triggers an instructive developmental program that does not require further antigenic stimulation and does not cease until memory CD8+ T cell formation.

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Figure 1: Varying the antigen dose affects the magnitude of the CD8+ T cell response and the recruitment of naïve CD8+ T cells, but all recruited cells divide extensively.
Figure 2: CD8+ T cells become committed to differentiate fully into effector CTLs after initial activation.
Figure 3: Activated CD8+ T cells continue to divide in the absence of antigenic stimulation in vitro.
Figure 4: Repeated exposure to antigen is not necessary for activated CD8+ T cells to divide several times and differentiate into effector CTLs in vivo.
Figure 5: IL-2 is important for activated CD8+ T cells proliferating in the ab-sence of continuous antigenic stimulation.
Figure 6: Activated CD8+ T cells are programmed to differentiate into long-lived, functional memory CD8+ T cells.
Figure 7: Memory CD8+ T cells generated in antigen-limiting conditions can confer protective immunity.
Figure 8: Models for proliferation and differentiation of naïve CD8+ T cells.


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We thank R. Antia, B. Evavold, G. Shadel and the Ahmed lab for helpful discussions and critical reading of this manuscript, H. Shen for the recombinant L. monocytogenes strain XFL203 and P. Mahar and K. Madhavi-Krishna for their technical assistance. Supported by National Institutes of Health grant AI30048 (to R. A.) and the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation, DRG-1570 (to S.M.K).

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Correspondence to Rafi Ahmed.

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Kaech, S., Ahmed, R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells. Nat Immunol 2, 415–422 (2001).

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