T-Cell Memory

T-cell activation results in a proliferative burst, effector cell generation, and then a dramatic contraction of cell number. At least 90% of effector cells die by apoptosis after pathogen is cleared, leaving behind an all-important population of antigen-specific memory T cells. Memory T cells are generally longer-lived than effector cells, and are quiescent. They represent about 35% of circulating T cells in a healthy young adult, rising to 60% in individuals over 70 years old.

Memory cells respond with heightened reactivity to a subsequent challenge with the same antigen. This secondary immune response is both faster and more robust, and hence more effective than a primary response.

Like naïve T cells, most memory T cells are metabolically quiet. They generate their energy from lipids via oxidative phosphorylation and are typically in the G₀ stage of the cell cycle. However, memory cells appear to have less stringent requirements for activation than naïve T cells. For example, naïve T cells are activated almost exclusively by dendritic cells, whereas memory T cells can be activated by macrophages, dendritic cells, and B cells. Memory cells express different patterns of surface adhesion molecules and costimulatory receptors that allow them to interact effectively with a broader spectrum of APCs. They also appear to be more sensitive to stimulation and respond more quickly. This may, in part, be due to epigenetic changes that enhanced access to genes required for activation. Finally, memory cells display recirculation patterns that differ from those of naïve or effector T cells. Some stay for long periods of time in the lymph nodes and other secondary lymphoid organs, some circulate among tissues, and some travel to and remain in peripheral organs, anticipating the possibility of another infection with the antigen to which they are specific.

Our ability to distinguish memory cells from naïve and effector cells, using surface markers, has improved dramatically and we now distinguish four broad subsets of memory T cells: central memory T cells (T_CM), effector memory T cells (T_EM), resident memory T cells (T_RM), and stem cell memory T cells (T_SCM). These differ in location, phenotype, and function. Recent work has also revealed a great deal of diversity within these subsets, whose relationships are still being clarified (Figure 10-15). We describe some useful generalizations below, and close with the many questions that remain.

FIGURE 10-15 One possible model for the development of memory T-cell subsets. This model, which is supported by multiple lines of evidence, suggests that activated T cells proliferate and differentiate progressively into stem cell memory T cells (T_SCM), central memory T cells (T_CM), and effector memory T cells (T_EM), which ultimately terminally differentiate into effector cells (T_EFF). As cells differentiate along this pathway they lose stem cell potential and become more differentiated. Resident memory T cells (T_RM) arise from several precursors and likely complete their differentiation in their tissue of residence. It is possible that some effector memory T cells also arise from fully differentiated effector T cells.

A na�ve T cell binds to an APC and differentiates into a T subscript SCM cell which in turn differentiates into a T subscript CM cell. The na�ve T cell, the T subscript SCM cell, and the T subscript CM cell are in the lymphoid tissues. The T subscript CM cell differentiates into a T subscript EM cell which in turn may differentiate into a T subscript EFF cell. The relationship between T subscript EM cell and T subscript EFF cell is still unclear. The T subscript EFF cells ultimately die. The T subscript EM cell and T subscript EFF cell reside in the peripheral tissues. T subscript RM cells reside in both lymphoid tissues and peripheral tissues. As the na�ve T cell progressively differentiates into the T subscript EFF cell, the self-renewal and memory potential decrease considerably whereas the differentiation potential increases.

Naïve, Effector, and Memory T Cells Can Be Distinguished by Differences in Surface Protein Expression

Four surface markers have been used to broadly distinguish naïve, effector, and various memory T-cell subsets in mice (Table 10-4):

• CD62L, an adhesion protein that regulates homing to secondary lymphoid organs
• CCR7, a chemokine receptor that also regulates homing to secondary lymphoid organs
• CD44, which increases in response to TCR-mediated activation signals
• CD69, a C-type lectin whose interactions prevent immune cells from leaving a tissue

TABLE 10-4 Surface proteins that are used to distinguish naïve, effector, and memory T cells

	Naïve	TEFF	TSCM	TCM	TEM	TRM
CCR7	+	-	+	+	-	-
CD62L	+	-	+	+	Variable	-
CD44	-	+	-	+	+	+
CD69	-	-	-	+	Variable	+
CD45RO (human)	-	-	-	+	+	+
CD45RA (human)	+	+	+	-	-	-
Fas (human)	-	+	+	+	+	+

The patterns of expression of these four molecules on T-cell subsets have a certain logic. Naïve T cells express low levels of CD44, reflecting their unactivated state, and high levels of the adhesion molecule CD62L, which directs them to the lymph nodes or spleen. In contrast, effector helper and cytotoxic T cells have the reciprocal phenotype. They express high levels of CD44, indicating that they have received TCR signals, and low levels of CD62L, which prevents them from recirculating to secondary lymphoid tissue, allowing them to thoroughly probe sites of infection in the periphery.

What about memory cells? Like effector T cells, all memory T cells express CD44, indicating that they are antigen experienced (i.e., have received signals through their TCR). Like naïve T cells, central memory cells (T_CM) express CD62L and the chemokine receptor CCR7, consistent with their residence in secondary lymphoid organs. Effector memory cells (T_EM), which are found in a variety of tissues, express varying levels of CD62L depending on their locale; however, they do not express CCR7, reflecting their travels through and residence in nonlymphoid tissues. Resident memory cells (T_RM) are distinguished by their expression of CD69, which prevents them from leaving a tissue. Those that reside in lymphoid tissue express CCR7; those that reside in the periphery do not.

The existence of memory T cells with stem cell potential (stem cell memory T cells or T_SCM) had been predicted for many years, but was confirmed only recently. These are rare cells that appear to be the least differentiated of all memory subsets. They share some features with naïve T cells, including low expression of CD44 and high expression CCR7 and CD62L. However, they also express markers that have been associated with memory cells, including Fas (CD95) and IL-2Rβ (CD122).

These surface markers represent only a starting point for understanding memory T-cell subsets (see Figure 10-15). Many others have also proven useful. For instance, human memory T cells are distinguished from naïve T cells by the expression of the RO, but not RA, variant of CD45, as well as by the expression of CD95 (see Table 10-4). CD8⁺ resident memory T cells often express CD103, an integrin that interacts with the epithelial membranes of barrier tissues. Other markers continue to reveal heterogeneity within the memory cell subsets, which promise to be as complex and interesting as the effector T-cell population.

Key Concepts:

• Memory T cells, which are more easily activated than naïve cells, are responsible for secondary responses. They can be distinguished from naïve and effector cells by differences in surface protein expression and function.
• Four types of memory T cells have been described: stem cell memory T cells (T_SCM), central memory T cells (T_CM), effector memory T cells (T_EM), and resident memory T cells (T_RM).

Memory Cell Subpopulations Are Distinguished by Their Locale and Effector Activity

Where are memory cells found? In general, T_CM cells reside in and travel between secondary lymphoid tissues. They live longer and have the capacity to undergo more divisions than their T_EM counterparts. They generate a high amount of IL-2, but much lower amounts of other effector cytokines. When they re-encounter their cognate antigen in secondary lymphoid tissue, they are rapidly activated and have the capacity to differentiate into a variety of effector T-cell subtypes, depending on the cytokine environment.

On the other hand, T_EM cells circulate among peripheral tissues (including skin, lungs, liver, and intestine). They secrete low levels of IL-2, but generate high levels of effector cytokines. They exhibit their effector functions rapidly when they engage their cognate antigen and are important early responders to re-infection.

T_RM cells are even better situated to respond immediately to re-infection. Permanent residents of tissues that have experienced infection, they patrol very actively, ready to respond as soon as there is a sign of re-infection (see Chapter 14). CD8⁺ T_RM cells have been best characterized, and can be found in multiple tissues, including skin, mucosa, and brain (see Chapter 13). CD4⁺ T_RM cells proved more difficult to locate and may circulate more readily. However, they have been found in multiple tissues, including the lungs and bone marrow.

Stem cell memory T cells are found in secondary lymphoid tissue and can develop into all other memory T-cell subsets. Importantly, as their name indicates, they are also self-renewing and provide a long-lasting source of T cells with proven utility.

Key Concepts:

• Memory T-cell subsets differ in location, circulation, and function.
• Central memory cells and memory stem cells are found in secondary lymphoid organs and have not committed to any particular effector lineage. They respond quickly and flexibly to re-infection.
• Effector and tissue-resident memory cells together provide a pool of rapid responders to peripheral tissues and quickly display their original effector functions after re-infection.

Many Questions Remain Surrounding Memory T-Cell Origins and Functions

Antigen-specific memory is the unique product of the adaptive immune system. It extends lives and is the biological basis for the success of vaccination. The better we understand memory, the better we might be able to harness it, and the better we may be able to design vaccines for diseases that still endanger humans and other animals. Yet immune memory has been slow to reveal its secrets and multiple questions remain.

How and When Do Memory Cells Arise?

Naïve CD4⁺ and CD8⁺ T cells proliferate robustly during the first few days of the immune response in secondary lymphoid tissue. Only a small proportion of the progeny of a naïve T cell commit to the memory cell lineages. Although multiple explanations have been advanced to explain how memory T-cell subsets arise, several lines of evidence favor a linear, progressive model of development (see Figure 10-15). In this scheme, naïve T cells give rise to a small number of memory stem cells, most of which continue to proliferate and give rise to central memory cells, most of which continue to proliferate and differentiate into effector memory cells, most of which terminally differentiate into effector cells. This model is consistent with the observations that the stem cell capacity and life span of memory subsets decrease progressively—from T_SCM, which are bona fide stem cells, through T_CM, which still have some ability to self-renew, to T_EM, the shortest lived memory population with little or no self-renewal capacity.

Some data raise other possibilities. Naïve cells may give rise directly to a heterogeneous population of effector and memory stem cells. Effector T cells may differentiate directly into effector memory T cells, which may also be precursors of central memory cells. Only time will tell which model(s), which are not necessarily mutually exclusive, holds up to scientific scrutiny.

The source of resident memory T cells is also not yet clear. They could arise from either or both central and effector memory T cells and are likely to complete their commitment in the peripheral tissues they end up in.

What Signals Induce Memory Cell Commitment?

Most investigators agree that T-cell help is critical to generating long-lasting memory of CD8⁺ T cells. Although CD8⁺ T cells can be activated in the absence of CD4⁺ T-cell help, this “helpless” activation event does not yield long-lived memory CD8⁺ T cells.

The relative importance of other influences in driving memory development is still under investigation. IL-7, IL-15, and the Wnt signaling pathway may all play a role in generating and maintaining T_SCM cells. IL-2 is important in generating effector memory T cells. Although strength and duration of antigen stimulation play an important role in memory cell commitment, recent data also suggest that even low-affinity interactions can generate memory T cells. All studies agree that the more proliferation a response inspires, the better the memory pool.

Do Memory Cells Reflect the Heterogeneity of Effector Cells Generated during a Primary Response?

We have seen that naïve T cells differentiate into a wide variety of effector T-cell subpopulations, largely determined by the cytokine signals they receive during activation. Studies indicate that the memory cell response is also very diverse, in terms of both the T-cell receptor specificities and the array of cytokines produced. However, the cellular origin of this diversity is still under investigation. Specifically, does this diverse memory response strictly reflect the functional effector diversity generated during the primary response? Or does it develop anew from central memory T cells responding to different environmental cues during rechallenge? The answer is likely to be “both,” but investigations continue.

How Do CD4⁺ and CD8⁺ Memory T Cells Differ?

Memory CD8⁺ T cells are more abundant than memory CD4⁺ T cells. This is partly because CD8⁺ T cells proliferate more robustly and therefore generate proportionately more memory T cells. It may also be due to differences in the life span of memory T cells: CD4⁺ memory T cells are not as long-lived as CD8⁺ memory T cells. CD4⁺ and CD8⁺ memory cells are likely to express different homing receptors and populate different layers of our barrier tissues. CD8+ memory T cells tend to be found in the epithelial layers (e.g., the epidermis of the skin and epithelium of the gut), whereas CD4+ memory T cells seem to prefer the deeper layers (e.g., the dermis of the skin and lamina propria of the gut). CD4+ memory T cells may also be more mobile. How these subpopulations coordinate their efforts during a secondary immune response is a topic of much interest.

How Are Memory Cells Maintained over Many Years?

Whether memory cells can persist for years in the absence of antigen remains controversial, although evidence seems to favor the possibility that they do. Regardless, it does seem that memory persistence depends on the input of cytokines that induce occasional divisions, a process known as homeostatic proliferation, which maintains the pool size by balancing apoptotic events with cell division. Both IL-7 and IL-15 appear important in enhancing homeostatic proliferation, but CD4⁺ and CD8⁺ memory T-cell requirements may differ.

Key Concepts:

• The generation of CD4⁺ and CD8⁺ memory T cells requires T-cell help. The more a naïve lymphocyte proliferates after activation, the better the memory response.
• Activated naïve T cells are thought to give rise directly to memory T-cell subpopulations that proliferate and differentiate in a linear fashion, culminating in the production of effector T cells. T_SCM give rise to T_CM, which give rise to T_EM, which terminally differentiate into effector T cells. Resident memory cells may arise from both T_CM and T_EM.
• The self-renewing potential and life span of memory T cells decrease as they differentiate from T_SCM to T_EM. T_SCM and T_CM circulate among secondary lymphoid tissue. T_EM circulate among peripheral tissues and T_RM take up permanent residence in peripheral tissues, ready to respond immediately if exposed to their cognate antigen.
• The regulation of memory T-cell development and response remains a very active area of investigation.