Making sense of inflammation, epigenetics, and memory CD8+ T-cell differentiation in the context of infection

Summary: Recent findings suggest a new paradigm that early inflammatory cytokines promote the effector T‐cell response while inhibiting the development of CD8⁺ T‐cell memory. Although this opposing effect may appear paradoxical at first, it makes biological sense in the context of an infection, by ensuring a maximal effector response that will clear the pathogen. Once infection is controlled, the withdrawal of inflammatory cytokines allows the differentiation of effectors into long‐lived memory cells that provide protective immunity against re‐infection. Memory T cells differ from naïve T cells in their responsiveness to stimulation, which leads to the rapid expression of effector functions. The molecular basis for enhanced functionality of memory T cells remains largely unknown. Recent results indicate that certain epigenetic changes are imprinted in memory T cells that play an important role in keeping them poised to respond immediately upon antigen re‐encounter. These epigenetic modifications occur as naïve T cells become activated and are influenced by factors that regulate memory formation. Thus, epigenetic changes are an integral component of memory T‐cell differentiation, while inflammation plays an unexpected regulatory role in the process. These advances in our understanding of T‐cell memory will undoubtedly help design unconventional vaccine strategies for inducing large populations of long‐lived and functional memory CD8⁺ T cells.     

Programming, demarcating, and manipulating CD8+ T-cell memory

Summary: In response to infection, antigen‐specific CD8⁺ T cells undergo massive expansion in numbers, acquire effector mechanisms, and disseminate throughout the body. The expansion phase is followed by a contraction (death) phase, where 90–95% of antigen‐specific CD8⁺ T cells are eliminated. The remaining antigen‐specific CD8⁺ T cells form the initial memory pool, which can be stably maintained for life. In this review, we discuss evidence that early events after infection ‘program’ CD8⁺ T cells to expand, contract, and generate memory in a fashion that is largely insensitive to the duration of infection or antigen display. Recent data demonstrate, despite numerical stability, that memory CD8⁺ T‐cell populations undergo phenotypic and functional changes with time after immunization. However, the early suggestion that specific markers can be used to identify memory CD8⁺ T cells has not been supported by recent studies. Thus, we argue that specific functional characteristics, such as the ability to persist and undergo vigorous secondary expansion leading to elevated memory cell numbers, remain the best markers of ‘good’ memory cells. Finally, we discuss experimental approaches to manipulate and accelerate generation of CD8⁺ T cells with memory characteristics, and how these systems can inform both basic and applied immunology.     

Generating long‐lived CD8+ T‐cell memory: Insights from epigenetic programs

T‐cell‐based immunological memory has the potential to provide the host with life‐long protection against pathogen reexposure and thus offers tremendous promise for the design of vaccines targeting chronic infections or cancer. In order to exploit this potential in the design of new vaccines, it is necessary to understand how and when memory T cells acquire their poised effector potential, and moreover, how they maintain these properties during homeostatic proliferation. To gain insight into the persistent nature of memory T‐cell functions, investigators have turned their attention to epigenetic mechanisms. Recent efforts have revealed that many of the properties acquired among memory T cells are coupled to stable changes in DNA methylation and histone modifications. Furthermore, it has recently been reported that the delineating features among memory T cells subsets are also linked to distinct epigenetic events, such as permissive and repressive histone modifications and DNA methylation programs, providing exciting new hypotheses regarding their cellular ancestry. Here, we review recent studies focused on epigenetic programs acquired during effector and memory T‐cell differentiation and discuss how these data may shed new light on the developmental path for generating long‐lived CD8⁺ T‐cell memory.     

Pathways of memory CD8+ T‐cell development

CD8⁺ T‐cell responses must have at least two components, a replicative cell type that proliferates in the secondary lymphoid tissue and that is responsible for clonal expansion, and cytotoxic cells with effector functions that mediate the resolution of the infection in the peripheral tissues. To confer memory, the response must also generate replication‐competent T cells that persist in the absence of antigen after the primary infection is cleared. The current models of memory differentiation differ in regards to whether or not memory CD8⁺ T cells acquire effector functions during their development. In this review we discuss the existing models for memory development and the consequences that the recent finding that memory CD8⁺ T cells may express granzyme B during their development has for them. We propose that memory CD8⁺ T cells represent a self‐renewing population of T cells that may acquire effector functions but that do not lose the naïve‐like attributes of lymphoid homing, antigen‐independent persistence or the capacity for self‐renewal.     

Regulators of T‐cell fate: Integration of cell migration,differentiation and function

A fundamental question in immunology is how cells decide between distinct T helper, effector or memory differentiation fates. These decisions are paramount to overcome infection and establish long‐lasting protection. The impact of cell location for the determination of T‐cell fate decisions is an emerging field. This review will discuss our current understanding of the migration path that T cells follow, within draining lymph nodes, to steer differentiation down distinct paths of either effector or memory fates. In particular, the regulation of migration and cellular encounters mediated by the chemokine receptor CXCR3 and its ligands will be discussed. The combination of increased antigen density and unique cellular partners play a central role in facilitating the site‐specific differentiation of effector T cells, within the interfollicular regions of draining lymph nodes. Recent advances have applied this knowledge to optimize vaccine design to target antigen to lymph nodes. Increased understanding of the regulation of CXCR3 ligands and how T cells integrate multiple chemokine cues will help further progress in this field and allow additional applications to direct cell differentiation outside the lymph node, to enhance memory residency in peripheral tissues and effector anti‐tumor responses.     

Early simultaneous production of intranodal CD4 Th2 effectors and recirculating rapidly responding central‐memory‐like CD4 T cells

This study characterizes the diversity of CD4 Th cells produced during a Th2 response in vivo. Kinetics of effector and memory cell differentiation by mouse OVA‐specific CD4 T cells was followed during primary responses to alum‐precipitated OVA. The complexity of the CD4 T response was assessed in nodes draining and distant from the site of immunization for phenotype, location and function. By 3 days IL‐4‐producing effector CD4 T cells developed in the draining node and a proportion of the responding cells had migrated to B‐cell follicles, while yet others had left the draining node. Some of these early migrant cells were recirculating cells with a central memory phenotype. These had divided four or more times in the draining node before migrating to distant nodes not exposed to antigen. We questioned the responsiveness of these early central‐memory‐like cells on secondary antigen challenge at sites distant to the primary immunization. They re‐entered cell cycle and migrated to B‐cell follicles, much more rapidly than naïve CD4 T cells and could still be induced to produce IL‐4. Their production and survival were independent of the starting frequency of antigen‐specific CD4 T cells. Thus intranodal effector cells and recirculating, rapidly responding central‐memory‐like cells emerged simultaneously from the third day of a primary Th2 response.     

CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza

Summary: We have outlined the carefully orchestrated process of CD4⁺ T‐cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T‐cell interaction with antigen‐presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4⁺ T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multifaceted roles of CD4⁺ effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4⁺ T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza.     

Similarities and differences in CD4+ and CD8+ effector and memory T cell generation

Naive CD4+ and CD8+ T cells undergo unique developmental programs after activation, resulting in the generation of effector and long-lived memory T cells. Recent evidence indicates that both cell-intrinsic and cell-extrinsic factors regulate memory T cell differentiation. This review compares and contrasts how naive CD4+ and CD8+ T cells make the transition to effector and/or memory cells and discusses the implications of these findings for vaccine development.