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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Semin Immunol. Author manuscript; available in PMC Oct 1, 2009.
Published in final edited form as:
PMCID: PMC2679806
NIHMSID: NIHMS106983

CD4 memory T cells: what are they and what can they do?

Abstract

Immunological memory provides the basis for successful vaccines. It is important to understand the properties of memory cells. There is much known about the phenotype and functions of memory CD8 T cells, less about memory B cells, while CD4 memory T cells have proved difficult to study. Differences in the types of memory CD4 cells studied and the difficulties of tracking the small number of cells has led to conflicting and unclear results. Here we discuss the different systems used to study CD4 memory cells and ask whether, and in what circumstances, memory CD4 cells could provide protection against infections.

Keywords: CD4, cytokine, help, memory, protection

Introduction

CD4 T cells play a central role in the immune system coordinating both adaptive and innate responses. CD4 memory T cells, however, have a much less well defined role, in fact their very existence is sometimes called into question [13]. Why is the subject of CD4 memory still so controversial? One of the major reasons for this is the variety of systems studied, and the different criteria used to define CD4 memory T cells. Here we discuss the appropriateness of a number of the systems used to study CD4 memory and, in light of this, examine how much we really know about the elusive CD4 memory T cell. Finally we would like to shift the focus away from the question of how exactly we define a CD4 memory T cell to the important, and sometimes over-looked question, of how memory CD4 T cells can provide protection against a variety of pathogens.

Upon exposure to antigen, for example during an infection or after vaccination, antigen specific T cells are activated, proliferate and differentiate into effector cells. The increased number of antigen specific cells with effector functions can act to clear the infection, but then, however, the vast majority of these cells die. The surviving cells are memory cells [4, 5]. These memory cells can provide protection or an enhanced response upon re-exposure to the same pathogen or antigen. The enhanced response is a consequence of two major changes following the initial exposure. First, although most of the activated cells die following the first response, the remaining cells are present at higher frequencies than the original naïve T cell. This higher frequency of antigen specific cells increases the likelihood that any re-infection will be detected quickly, allowing the immune response to get underway before the pathogen has time to spread.

The second difference between naïve and memory cells is that memory cells are able to make effector responses more rapidly than primary responding cells [6, 7]. Depending on the type of infection and the signals relayed from antigen presenting cells, such as dendritic cells (DC), the responding T cells can make a range of responses. The number of CD4 T cell subsets has grown in recent years to include not just T helper (Th) 1 and Th2 cells but also Th17 cells and regulatory T cells (Treg) [8]. Th1 cells predominately make inflammatory effector cytokines such as interferonγ (IFNγ) and tumor necrosis factorα (TNFα) that are required for clearances of viruses and intracellular bacteria [9, 10]. Th2 cells can make a number of interleukins (IL) including IL4, IL5 and IL13 and are implicated in protection against helminth parasite [9, 10] but also play a role in allergic responses [11]. The more recently identified Th17 cells are thought to be involved in protection against extracelluar bacteria but also play a role in autoimmunity [12, 13]. Treg can either be generated in the thymus (natural Tregs) or can be generated during immune responses (inducible Tregs) [14]. The properties and functions of Tregs have been extensively reviewed elsewhere [15, 16] and so will not be discussed further in this review.

Memory cells can be distinguished from naïve cells based on a number of cell surface molecules and these alterations are often used to define memory cells [4, 5]. Whether these changes are sufficient to define memory cells is discussed below. Changes in cell surface molecules following T cell activation include the upregulation of the receptor for hyaluronate, CD44. This may allow activated and memory T cells to enter inflamed peripheral sites where an infection could be present [17]. In humans, changes in the isoform of CD45 that are expressed are often used to differentiate naïve and memory cells with naïve cells expressing CD45RA and memory cells expressing CD45RO [5].

T cell activation results in the downregulation of CD62L and CCR7, molecules that are required to enter lymph nodes and access the T cell area of the lymph node, respectively. While the changes in CD45 expression and the upregulation of CD44 are probably permanent changes, some memory cells re-express CD62L and CCR7. This has led to the description of two subsets of memory cells. First described in the peripheral blood of humans [18], T central memory cells (TCM) cells are similar to naïve T cells in that they express CD62L and CCR7 and make IL2 following re-activation. T effector memory cells (TEM) cells make effector cytokines (such as IFNγ or IL4) and are less likely to traffic through lymph nodes due to their low expression of CD62L and CCR7. Although there is evidence for the existence of these subsets, in other reports the distinction is less clear [1925]. In mice, protection from re-infection appears to be best provided by TCM CD8 T cells [26]. Whether the same is true for CD4 T cells is an area of debate [27].

Not all memory cells are equal

Before we can understand what role CD4 memory T cells can play in protective secondary responses, it is important to have a clear definition of what they are. Can the term memory be used loosely to describe any T cell that does not have a naïve phenotype? Or, at the other end of the spectrum, is it critical to know the specificity of the TCR and thereby have some understanding of what the stimulating antigen and activation environment was?

CD4 memory cells have been difficult to study because, unlike CD8 T cells, they are not usually present in large numbers after exposure to antigen [28, 29]. Therefore CD4 memory cells are often studied in the form of “memory phenotype” cells from animals that have not been intentionally immunized with antigen but which nevertheless bear the surface markers expected of memory cells e.g. high levels of CD44, low levels of CD62L and changes in the isoform of CD45 that are expressed (Table 1, [3032]). These cells have the advantages that they are available in reasonably large numbers from unmanipulated individuals and can easily be isolated. The major disadvantages of using these cells is that their antigens are unknown and, indeed, they may not have been created by reaction with antigen at all [33].

Table 1
Models for studying memory CD4 T cells in mice.

The proportion of memory phenotype CD4 and CD8 T cells increases with age in both mice and humans [30]. In mice kept in specific pathogen free conditions the origin of these cells is particularly unclear. Some of these cells may be a result of proliferation of the first T cells that leave the thymus and enter a lymphopenic environment [34], although proliferation in neonates does not always lead to the upregulation of CD44 [35]. Memory phenotype cells may also be generated as a result of exposure to environmental antigens and in this case they may not have received the costimulatory signals considered necessary to generate bona fide memory cells. Although memory phenotype cells can have properties similar to those of genuine memory cells [3032], their unknown history makes any data based on them questionable. Humans are exposed to many more antigens, and this is more likely to occur in inflammatory settings. Therefore, human memory phenotype cells are likely to contain many antigen-elicited, genuine memory cells. Indeed, these cells do act like memory cells in many regards [3639].

To circumvent the problem of the unknown specificity of memory phenotype cells, T cells expressing a transgenic T cell receptor (TCR Tg) can be used (Table 1). Memory cells can be generated by the transfer of small numbers of TCR Tg cells to wild-type mice that are subsequently immunized or infected. However, if small numbers of TCR Tg cells are transferred, this does not solve the problem of how to detect and isolate the memory cells. To surmount this problem, cells have either been transferred at very large frequencies, transferred into lymphopenic hosts, or transferred after activation in vitro [7, 19, 20, 40, 41]. A number of artifacts have recently been described by several groups following the transfer of large number of TCR Tg cells [4245] demonstrating that this is not the most useful way to study memory T cells. The transfer of TCR Tg cells to lymphopenic hosts provides a straight-forward way in which to generate large numbers of memory cells that can easily be re-isolated. However, these cells are generated (regardless of whether they were activated in vivo or in vitro prior to transfer) and maintained in very artificial environments.

The advent of both human and mouse MHC (major histocompatibility complex) class I and II tetramers have enabled the counting and phenotypic analysis of endogenous memory cells ex vivo. First generated by Altman and co-workers, MHC tetramers have revolutionized T cell immunology [46]. Class I tetramers are now widely used; class II tetramers, on the other hand, have proved to be more challenging both to produce, and to use to track the smaller number of responding CD4 T cells. Several groups (including our own) have now successfully produced and used human and mouse MHC class II tetramers to examine CD4 T cells and their responses [4754]. There are two major drawbacks to using MHC tetramers to track T cell responses (Table 1). The first is that it is essential to know the T cell epitope(s) from the protein(s) of interest, although this is becoming easier as our knowledge of the binding patterns of peptides to the MHC improves [55, 56]. The second hurdle is that once one epitope has been determined and MHC tetramers produced, examining the T cell response to this one epitope may not provide a complete picture of a response, especially if a complex microorganism is studied.

In summary, we believe that there are certain criteria that must be met for a memory cell to be considered a genuine memory cell. Most important is the knowledge of the specificity of the T cell and the environment in which the T cell was activated. In experimental animal models, this means that the animal has been intentionally exposed to an antigen or infection. That the T cell is activated in vivo in an animal with a full lymphoid compartment, is also key, ensuring that the activation and subsequent generation of the memory cell occurs normally. In humans, genuine memory cells can be identified with MHC tetramers that recognize antigen-elicited T cells, for example from pathogens or vaccines to which the individual has been exposed. In our eyes, there is little reason to continue to study memory phenotype cells when it is clearly feasible to study genuine memory cells [4754].

The controversy

CD4 T cell memory has always been a controversial issue. The controversies cover a wide range of problems including: how memory cells are generated (stochastic vs selected); how and to what extent (if any) they are maintained over time; how many subtypes exist; and what role (if any) they play in protecting the host from re-infection?

Zinkernagel has long argued that the presence of long-lived antigen specific cells does not test the presence of protective memory, that the only way to test for memory is with the use of survival assays [1, 2]. Zinkernagel and Hengartner propose that protection is provided either by pre-existing neutralizing antibodies or by T cells that are “pre-activated,” a characteristic that requires the presence of persistent antigen [2]. Whether cells that are continuously exposed to antigen can be considered memory cells is more than a question of semantics. Certainly cells that actively “see” their antigen will have a different phenotype than cells not exposed to antigen. This persistent antigen may not necessarily be a good thing as CD4 and CD8 T cells exposed to antigen continuously can become exhausted and/or anergic [5759]. However, in some settings persistent antigen may be important in the continual generation of memory cells [59], or in the maintenance of certain memory cell phenotypes [60].

Bell and Westermann have recently argued that the CD4 T cells that survive following an immune response cannot be considered “memory” cells as they are not permanently altered by the activation process either in terms of phenotype or function [3]. Rather, they suggest that the “memory” response is just a function of the increase in the precursor frequency of antigen specific cells after an immune response and that these cells reside in the “naïve” T cell compartment. We and others have found the opposite to be true: long-lived antigen specific cells, identified by MHC class II tetramers, are CD44hi [47, 48, 6163]. Bell and Westerman make the intriguing suggestion that re-expression of the heavily glycosylated naïve isoform of CD45 prevents MHC tetramers from binding to and identifying “memory” cells with a naïve phenotype [3]. This seems unlikely as naïve T cells can be stained with MHC tetramers [47, 52, 64]. Certainly antigen specific CD4 T cells can be identified for some time following an immune response but how well they are maintained is an issue that has not yet been resolved.

By examining memory phenotype cells or memory TCR Tg cells, many characteristics of memory cells have been described. For example, it is clear that memory cells are activated more rapidly than naïve cells, that they are more likely to make effector responses and require lower doses of antigen and costimulatory signals than primary responding cells, and they are more likely to be found in tertiary organs [7, 19, 6567]. However, it is important to make the distinction between intrinsic differences between memory and naïve cells and the consequences of just having more cells specific for a particular antigen. When using TCR Tg cells this problem can be easily resolved as equal numbers of the naïve and memory cells can be examined. However, as mentioned above, there are major caveats to experiments involving the transfer of large numbers of TCR Tg cells [4245].

Numerous convincing studies have demonstrated that memory cells are intrinsically different from naïve cells. For example, Chandok et al. showed that the levels of the molecules required for TCR signaling are increased in memory CD4 T cells as compared to naïve cells, enabling the memory cells to respond more quickly to antigen [65]. Using cytokine reporter mice, Mohrs et al. showed that, following antigen-exposure, memory CD4 T cells expressed mRNA for the effector cytokine, IL4, and upon rechallenge, these cells made IL4 protein more quickly than primary responding cells [68]. These two studies demonstrate two of the classic features of memory cells: they respond more rapidly and their response is dominated by production of effector cytokines. The third classic feature of memory responses is that they are larger than primary responses. We have recently made the somewhat surprising observation that memory CD4 T cells do not proliferate for as long a time as naïve T cells as a consequence of changes in cytokine production [47], thereby explaining the earlier peak response of memory cells. This may also be due to direct inhibition of memory responses by presentation of peptide-MHC complexes by the responding memory CD4 T cells to each other [69]. Therefore, the larger size of memory responses is dependent on their increased number, not their ability to produce more progeny. This means that, if memory CD4 T cells decline over-time, the size of the recall response will be proportionally reduced.

The controversy continues: antigen and memory cell survival

The long-term survival (or absence thereof) of CD4 memory cells is one of the memory CD4 field’s most problematic subjects. For example, whether antigen is required to maintain memory cells has been a long-standing controversy. Initially, Gray and Matzinger found that continued exposure to antigen was required for rat antigen specific memory CD4 cells to maintain their ability to help B cells [70]. However, the finding that in vitro activated CD4 TCR Tg cells could survive following transfer to MHC class II deficient animals, suggested that memory cells could survive in the absence of TCR signals [71]. There are some major caveats to this latter study. Significantly, there are no other CD4 T cells in an MHC class II deficient host, so the transferred memory cells survived in an artificial environment in which there was no competition for survival with other CD4 T cells, for example for the important cell survival cytokine, IL7 [31, 72, 73]. Moreover, it has now been shown that although transferred CD4 memory cells can survive in MHC class II deficient hosts, they are functionally impaired in the absence of the tonic TCR signals provided by interactions with MHC II [74]. Thus, in such experiments it is important to evaluate not just the presence of memory cells but also their function.

Importantly, when examined in non-lymphopenic mice, antigen specific CD4 memory T cells have been found to decline [4749, 63] and the numbers of specific CD4 T cells in humans decline faster than specific CD8 T cells or B cells [75, 76]. These studies suggest that, even if there is a specific survival signal for memory CD4 T cells, the cells are unable to achieve a long-term survival advantage. A recent study from Hataye et al. made the intriguing suggestion that memory cells not only require contact with MHC class II for survival but also compete for signals derived from this contact [43]. This conclusion was reached from the finding that both naïve and memory TCR Tg cells decline in wild-type hosts at much greater rates following the transfer of large numbers of T cells compared to the transfer of very few cells. Duffy et al. reported the same phenomenon but in their case the faster decline of the same TCR Tg cells was caused by rejection by the wild-type host, with the transfer of more cells inducing an enhanced response against the transferred TCR Tg cells [77]. The lesson from these studies is that data based solely on TCR Tg cells may contain pitfalls and any results should be confirmed using antigen specific endogenous memory CD4 T cells.

Although overt antigen may not be absolutely required for CD4 memory cell survival, it may be important for the phenotype and location of the cells. Cells in peripheral organs such as the lung or the peritoneal cavity have a different phenotype from cells in lymphoid organs [63, 66]. However, the migration of the memory cells to these peripheral sites, rather than persistent antigen, may be what causes the activated phenotype [66]. As Zinkernagel and Hengartner argue, antigen may be required to maintain certain T cell functions [2]. For example, the presence of persistent antigen in the draining lymph node caused T cells to maintain high levels of ICOS and CXCR5, indicative of the T follicular helper subset [60]. Therefore, persistent antigen may have an important role to play in maintaining the helper activity of some T cells.

In some cases CD4 cells are potentially constantly exposed to antigen, for example in chronic infections. Although the repeated exposure to antigen can diminish the effector function of CD4 T cells [59], IFNγ producing CD4 cells have been shown to play an important, although as yet unclear, role in preventing re-activation of the herpes virus, γ-herpes virus [78]. Whether these T cells, which are actively involved in an on-going immune response, can be called memory cells rather than effector cells, is a debatable question.

Can CD4 memory T cells provide protective responses?

Rather than define memory based on cell surface phenotype, perhaps a more useful way is by an alteration in the response following a second exposure to the antigen; demonstrating function, rather than just counting numbers of cells. This leads to the more important question of whether memory CD4 T cells can provide a protective response. It is clear that the humoral response and CD8 T cell responses can be protective in both human and mouse infection models. For example, protective antibody can be measured many years after infection or vaccination [75, 76, 79]. Similarly, CD8 memory responses can often be examined by measuring ex vivo cytotoxicity, or in the mouse by challenge infections [80, 81].

There are several ways in which memory CD4 T cells could be protective. 1. by making effector cytokines early in the response and in large quantities, 2. by enhancing B cell responses 3. by enhancing CD8 T cell responses and 4. by directly killing infected cells, Figure 1

Figure 1
Memory CD4 T cells could protect the host in a number of possible ways.

1. Early effector cytokines

Mycobacterium Tuberculosis (TB) latently infects one third of the world’s population and causes the death of around 2 million people every year [82, 83]. The current vaccine, BCG (Bacillus Calmette-Guérin), provides varying levels of protection [84] but is thought to act by generating IFNγ producing CD4 T cells that activate infected macrophages in the lung, enabling them to kill the bacteria [85, 86]. The presence of long-lived TB specific CD4 memory cells can be demonstrated by the tuberculin skin test that contains small amounts of TB proteins and causes a type IV hypersensitivity reaction in vaccinated or infected individuals.

In mouse models of TB, CD4 memory cells provide a small level of protection in mice either immunized with BCG or infected, then drug-cured, with TB itself [87, 88]. Although a difference in bacterial growth between normal and vaccinated mice is observed only after day 15 of infection, protection correlates with an early increase in type 1 cytokine production (including TNFα and the chemokines IP-10 and MCP-1) and the presence of IFNγ producing CD4 cells in the lungs [87].

Interestingly, this is not accompanied by a large increase in the number or IFNγ producing cells in the lung, suggesting that large numbers of antigen specific cells may not be needed for the protective effect. It is perhaps not surprising, therefore, that a large number of in vitro activated TCR Tg cells were able to provide only limited protection following transfer to mice subsequently infected with TB [89]. Goldsack and Kirman argue that IFNγ production by CD4 cells is not sufficient to provide protection from TB and suggest that it is important to consider other protective mediators [83]. For example, Khasder et al. have reported a critical role for IL17 producing CD4 cells in the amplification of the T cell response to TB in the lung [90].

A clearer role for CD4 produced IFNγ has been shown in other bacterial models. IFNγ producing CD4 cells generated by vaccination with specific antigen and adjuvant provide protection from either Chlamydia muridarum or Bacillus anthracis [91, 92]. Although promising, in both studies the CD4 cells examined may well be effector rather than memory cells either because of the time between the last vaccination and the challenge [91] or because the experimenters used an adjuvant that induces a depot of antigen [92].

Th2 memory cells can also provide protection, for example in mice first infected and then drug-cleared with the Helminth parasite Heligmosomoides polygyrus [93]. In this case, the rapid IL4 response by the memory CD4 T cells results in an increase of alternatively activated macrophages in the gut that act as effector cells in parasite clearance. The rapid production of IL4 in the recall response to H. polygyrus was elegantly demonstrated by Mohrs et al. who used IL4 reporter mice to show that IL4 protein is made in the lamina propria just a few days after reinfection [68].

The protective role of cytokine producing memory CD4 T cells in humans is much more difficult to demonstrate. IFNγ and TNFα producing vaccinia specific and IFNγ producing measles specific CD4 T cells can be found in individuals many years after immunization with the viruses [75, 76]. However, protection from these viruses is probably provided by antibody (reviewed in [94, 95]).

More relevantly, a correlation was found between the presence of IFNγ producing CD4 T cells specific for a malaria protein and a reduced incidence of malaria, suggesting that these cells provided some protection to re-infection [96]. Th2 cells may be important in humans for protection against parasitic worms that reside in the gut [97] and, although protection following drug-treatment from the helminth, Schistosoma mansoni, is correlated with Th2 responses [98], natural protection appears to involve a mixed Th1/2 response [99].

It has recently become clear that protective T cell responses may depend more on the quality of the cytokine producing cell rather than just on the presence of cells that can make the appropriate cytokine response. Several recent studies have described the presence of “multipotent” cytokine producing memory CD4 T cells [22, 27, 100, 101]. These cells make a range of cytokines, such as IFNγ, TNFα and IL2 and often make higher levels of cytokine than single-cytokine producing cells. Importantly, the presence of multipotent cytokine producing cells correlates with protection in both Leishmania [100] and vaccinia [101] infection models in mice.

These studies suggest that the critical factor for generating protective CD4 memory T cells would be to induce effector memory cells making the appropriate cytokine response, IFNγ for Th1 responses such as influenza or tuberculosis, IL4 for Th2 responses such as helminth infections. There had been some evidence that cytokine producing cells in the primary response could not develop into memory cells [40], suggesting that vaccines should aim to generate TCM cells rather than TEM cells. However, two recent studies have convincingly shown that cells making IFNγ in the primary response can survive into the memory pool [102, 103] and cells that have activated their IL4 locus during priming can also become memory cells [104]. Therefore, it seems likely that vaccines should aim to induce T cells that can make the appropriate cytokine response for the infection they are designed to protect against.

2. Memory CD4 help for B cells

Most vaccines act by producing long lived antibody producing cells and the same may be true for the long lived protection that is afforded by natural infections. It is clear that CD4 T cells are critical for the majority of primary B cell responses, particularly to protein antigens. By providing help via cytokine production (such as the antibody isotype switch factors IL4 and IFNγ) and cell surface molecules (e.g. CD40L and ICOS), CD4 T cells enable B cells to form germinal centers, class switch and undergo affinity maturation [105]. What is less clear is whether CD4 T cells (and in particular antigen specific memory CD4 T cells) are required for memory B cell responses.

Various experiments and observations have demonstrated that CD4 T cells are not required for the long-term maintenance of memory B cells/and or antibody release by plasma cells. There is clear evidence that humoral immunity steadily persists for many years while CD4 T cell memory declines [75, 76, 79]. Moreover, in HIV infected individuals, humoral immunity to infections and vaccines encountered prior to HIV infection, is maintained despite a decline in CD4 T cells [106, 107].

To answer this question more directly, Vieira and Rajewsky depleted CD4 cells in previously immunized mice [108]. Although the memory B cells persisted in the absence of T cells, they were unable to make a secondary antibody response. These results suggested that CD4 T cells were required to help memory B cells respond to antigen.

In contrast to this finding, Hebeis et al. found that, following the transfer of memory B cells to Rag knockout mice, B cells responded equally to re-activation regardless of the presence of transferred immune CD4 cells [109]. The explanation for this difference probably lies in the different forms of antigen used in the two studies. While Vieira and Rajewsky used soluble antigen, Hebeis et al. used particulate antigen. In support of this, while Duffy et al. found that memory B cells needed CD4 T cell help to produce antibody in response to soluble ovalbumin (OVA) [110], in a separate study, memory B cells activated with OVA and alum (forming a particulate antigen), did not require T cell help [111]. Surprisingly, Duffy et al. found that help could be provided by the transfer of the same number of naïve and memory TCR Tg cells, suggesting that memory CD4 cells are no better than primary responding cells at helping B cells [110]. However, this may be a consequence of the way in which the CD4 memory cells were generated in this study. Memory cells were generated following the transfer of naïve cells into SCID recipients that were subsequently immunized. Perhaps in this lymphopenic environment, the memory cells lose some of their helper activity, indeed, there is some evidence that memory CD4 T cells require the presence of B cells in order to survive long term [112].

Although these studies examined the cellular requirements for memory B cell responses, the more relevant question is whether memory CD4 T cells can provide help to B cells to produce neutralizing antibodies during infection. Gupta et al. asked this question by examining the antibody response in mice primed with one serotype of vesicular stomatitis virus (VSV) and then challenged with a second serotype [113]. This is an example of heterosubtypic immunity in which the two serotypes shared common T cell epitopes but required different antibody responses to neutralize them. Although the VSV specific CD4 memory T cells could enhance primary antibody responses to a hapten that had been conjugated to the virus, they were unable to enhance primary neutralizing antibody responses. This result suggests that while the CD4 T cells were capable of enhancing some antibody response, they were unable to improve a useful antibody response to the neutralizing epitope.

The ability of CD4 T cells to mediate heterosubtypic immunity is a salient issue with the threat of a pandemic influenza infection looming [114]. Protection from influenza is thought to be largely mediated by neutralizing antibodies to the two main surface proteins, haemagglutinin and neuramindase [114]. However, as a consequence of poor proof-reading by the viral polymerases (antigenic drift) and the reassortment of viral genes from different serotypes (antigenic shift), these molecules frequently change, rendering the neutralizing antibodies potentially useless. Heterosubtypic immunity has been demonstrated in mouse models of influenza infection such that mice previously exposed to one subtype of virus have some level of protection from infection with a different subtype [115, 116].

Although heterosubtypic immunity has not been convincingly demonstrated in humans, there is some evidence that adults exposed to previous influenza infections are less likely to fall sick with new influenza variants [117]. A number of CD4 epitopes have been found in common between different subtypes of influenza, even between recent variants and H5N1, the subtype that causes bird ‘flu and has been predicted to be a potential cause of an influenza pandemic [55, 118, 119]. However, the significance of identifying these epitopes can be called into question if CD4 memory T cells generated from a previous influenza infection are unable to provide protection from the new infection.

From early studies, heterosubtypic immunity to influenza was thought to be mediated by both CD4 and CD8 T cells, although this protective effect was found to wane over time [115]. A more recent study by Rangel-Moreno et al. demonstrated that, in mice, heterosubtypic immunity relies on a number of mechanisms involving CD8 T cell and B cell responses [116]. Although not directly tested in this study, the authors did not observe an enhanced primary B cell response to influenza in the presence of potentially cross-reactive CD4 memory T cells, suggesting that CD4 T cells may play, at most, a minor role in heterosubtypic immunity to influenza.

It is theoretically possible for CD4 T cells to provide protection from influenza. Brown et al. have examined the ability of in vitro activated CD4 TCR Tg cells to provide protection from influenza challenge in mice [120]. The transfer of large numbers of the activated cells could protect mice and the authors showed that this was partly as a result of enhanced B cell responses as the ability of the T cells to provide protection was reduced following transfer to B cell deficient mice. It still remains to be demonstrated, however, whether small numbers of antigen specific memory CD4 T cells could achieve the same level of protection.

A further concern about studies that use in vitro activated cells is that the range of T cell phenotypes generated in vivo may not be reflected in this population. Although influenza virus induces a type 1 immune response, it may be more appropriate to generate T follicular helper memory cells if the aim is to enhance the B cell response [121]. Moreover, TGFβ producing memory T cells, rather than Th1 cells, may be required to enhance a protective IgA response to influenza [122, 123]. Therefore, any vaccine designed to generate memory CD4 T cells with the intention of having them help B cells, must consider what type of B cell is required to protect the host from the infection.

3. Memory CD4 help for CD8 T cells

CD4 T cell help is not exclusively for B cells. Many studies have shown that CD4 T cell help improves the production and/or function of CD8 memory T cells (reviewed in [124]). However, there does not seem to be a requirement for antigen specific memory CD4 T cells [125]. A question that has been less well studied is whether memory CD4 T cells can enhance a primary CD8 T cell response. Krawczyk et al. examined this question by first priming mice with DC loaded with the immunodominant CD4 T cell epitope from Listeria monocytogenes, then challenging the mice with a recombinant L. monocytogenes expressing OVA [126]. The presence of the CD4 memory cells resulted in an increase in the number of SIINFEKL-specific CD8 T cells and also significantly reduced the number of bacteria found in the spleen following challenge. This study suggests that the role CD4 memory T cells may play in protecting the host could extend beyond the obvious enhancement of antibody responses.

4. Killer CD4 T cells

Finally, CD4 T cells can act to reduce a secondary infection by directly killing infected cells. There are a number of mechanisms by which T cells can kill, including Fas-FasL interactions or via the release of granzyme B and perforin [127]. Peforin-mediated killing is more generally thought to be a function of CD8 T cells, however, there are a number of studies that show that CD4 T cells can also kill in this way. Early studies demonstrated killing by CD4 cells using cells cloned from infected mice [128] or from humans [129, 130]. Although there is some concern that this could be an in vitro artifact [131], a study by Erb et al. demonstrated that cytotoxic CD4 T cells could be found ex vivo [132].

More recent studies have examined cells directly ex vivo or in vivo. Human memory CD4 T cells were found to express perforin in healthy individuals and such cells were increased in HIV infected individuals [133]. These cells expressed surface markers indicative of end-stage differentiation, suggesting that “killer” CD4 memory cells may be generated by a strong activation stimulus. However, there is no indication whether these cells were involved, let alone required, for protective immune responses. One indication that these cells could be protective comes from Adhikary et al., who showed that cytotoxic human Epstein Barr Virus specific CD4 clones could control the virus in vitro [134].

In mice, the in vivo presence of cytotoxic CD4 T cells has been demonstrated following infection with lymphocytic choriomeningitis virus (LCMV) [127]. These T cells could kill transferred cells that had been pre-pulsed with a CD4 LCMV epitope either via Fas-FasL interactions or by perforin. It is still unclear, however, whether these killer CD4 cells were required for, or play a role in, protection. Certainly LCMV specific memory CD8 T cells can clear the infection rapidly in the absence of a memory CD4 T cell response [135]. Perforin producing CD4 T cells have been shown to be partly responsible for the protection offered by the transfer of large numbers of activated CD4 T cells to wild-type hosts subsequently infected with influenza [120]. However, this effect was lost if fewer cells were transferred. It remains to be determined, therefore, whether memory CD4 T cells present at normal frequencies could act in this way.

Conclusions

That CD4 memory T cells exist seems clear. Present in an altered state and at higher frequencies following an immune response, these cells have the hallmarks of memory. Whether, as a population, they are long-lived is less clear, prompting the question of why would the individual not want to maintain the CD4 memory T cells that have been generated following a successful immune response? Perhaps the simple answer to this question is that there has been no selective pressure to preserve memory CD4 T cells, they are simply not needed once long-lived protective antibody and CD8 T cells have been generated. Certainly, if CD4 memory T cells can only provide protective responses when present at high frequencies, their poor long-term survival is an area of important concern.

What is also not clear is what role CD4 memory T cells can play in protective responses. CD4 T cells are central to all adaptive immune responses. It seems unlikely to us then, that memory CD4 T cells do not have an important role to play in at least some infections. The lack of reliable and successful vaccines against some of the world’s deadliest infections prompts a re-examination of how memory T and B cells can offer protection to the host. Since CD4 T cells can direct so many other immune cells, they seem likely to be critical mediators in protective immune responses. The big question for the memory CD4 T cell field now is not whether memory CD4 T cells exist, but what CD4 memory T cells can do to protect infected or vaccinated individuals and, perhaps more importantly, to ask how memory cells capable of protection can be effectively generated.

Acknowledgments

We thank Frances Crawford for critical reading of the manuscript. This work was supported by NIH grants: NIH-AI-18785, AI-22295, AI-52225.

Abbreviations

BCG
Bacillus Calmette-Guérin
DC
dendritic cell
IFNγ
interferon gamma
IL
interleukin
LCMV
lymphocytic choriomeningitis virus
OVA
ovalbumin
TB
tuberculosis
TCR Tg
T cell receptor transgenic
TGFβ
transforming growth factor beta
TNFα
tumor necrosis factor alpha
VSV
vesicular stomatitis virus

Footnotes

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