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Review
. 2021 May 3;13(5):a038661.
doi: 10.1101/cshperspect.a038661.

CD8+ T-Cell Memory: The Why, the When, and the How

Stephen J Turner  1 , Taylah J Bennett  1 , Nicole L La Gruta  2
Affiliations
Review

CD8+ T-Cell Memory: The Why, the When, and the How

Stephen J Turner et al. Cold Spring Harb Perspect Biol. .

Abstract

The generation of effective adaptive T-cell memory is a cardinal feature of the adaptive immune system. The establishment of protective T-cell immunity requires the differentiation of CD8+ T cells from a naive state to one where pathogen-specific memory CD8+ T cells are capable of responding to a secondary infection more rapidly and robustly without the need for further differentiation. The study of factors that determine the fate of activated CD8+ T cells into either effector or memory subsets has a long history. The advent of new technologies is now providing new insights into how epigenetic regulation not only impacts acquisition and maintenance of effector function, but also the maintenance of the quiescent yet primed memory state. There is growing appreciation that rather than distinct subsets, memory T-cell populations may reflect different points on a spectrum between the starting naive T-cell population and a terminally differentiated effector CD8+ T-cell population. Interestingly, there is growing evidence that the molecular mechanisms that underpin the rapid effector function of memory T cells are also observed in innate immune cells such as macrophages and natural killer (NK) cells. This raises an interesting hypothesis that the memory/effector T-cell state represents a default innate-like response to antigen recognition, and that it is the naive state that is the defining feature of adaptive immunity. These issues are discussed.

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Figures

Figure 1.
Figure 1.
Phenotype, function, and location of T-cell memory subsets. Memory CD8+ T cells are found in circulation, lymphoid, and non-lymphoid peripheral tissues. Tcm and Tscm cells have high self-renewal capacity and express CD62L and CCR7, enabling them to traffic to secondary lymphoid organs from the circulation. Tem cells are migratory, trafficking from the circulation to survey non-lymphoid peripheral tissues. Whereas they have limited proliferative and self-renewal capacity, Tem cells rapidly produce cytokines and cytotoxic molecules upon TCR stimulation. Tpm cells can also enter non-lymphoid peripheral tissues and exhibit functional capacity like Tem, but they have proliferative capacity akin to Tcm. Unlike these other memory subsets, Trm cells are tissue restricted and can provide a rapid front-line defense in tissues such as the skin, gut, and lung. Tvm cells are found in the blood, secondary lymphoid tissues, and non-lymphoid tissue such as the liver under steady-state conditions. Whereas they are antigen naive, they are semi-differentiated and rapidly proliferate and produce effector molecules upon TCR stimulation.
Figure 2.
Figure 2.
Epigenetic control of effector gene loci enables memory CD8+ T cells to elicit rapid effector functions upon secondary infection. Effector genes (such as Ifng) in naive CD8+ T cells are characterized by inaccessible chromatin structure and repressive epigenetic marks, such as H3K27me3. This dense chromatin structure ensures that effector gene loci are inaccessible to RNA pol II and transcriptional machinery in the naive state. Upon primary infection and activation, remodeling of the chromatin landscape and deposition of active epigenetic marks such as H3K4me3 and H3K4ac at effector gene loci permits transcription. Memory CD8+ T cells retain this permissive chromatin structure with RNA pol II docked and are thus poised to rapidly transcribe effector genes upon secondary infection. (TF) Transcription factor.
Figure 3.
Figure 3.
Epigenetic control of effector versus memory fate. The naive T-cell state is maintained by the transcription factor TCF-1 (encoded by Tcf7), which establishes a permissive chromatin landscape around the Tcf7 locus, forming a feedforward loop. Upon primary infection and activation, Tcf7 expression is repressed. Expression of EZH2 (the catalytic component of PRC2) and SUV39H1 in recently activated CD8+ T cells plays a role in determining effector versus memory fate. PRC2 mediates methylation of H3K27, a repressive epigenetic mark enriched at pro-memory gene loci in effector CD8+ T cells. SUV39H1 mediates methylation of H3K9, another repressive epigenetic mark. In the absence of SUV39H1, pro-memory genes are not epigenetically repressed, and the effector program cannot be fully engaged. PRC2 and SUV39H1 likely function in recently activated CD8+ T cells to silence genes that promote memory formation, thus opposing memory fate and enabling effector differentiation.
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