PerspectiveImmunology

CD8 T Cells Remember with a Little Help

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Science  11 Apr 2003:
Vol. 300, Issue 5617, pp. 263-265
DOI: 10.1126/science.1084511

Memory T and B lymphocytes of the immune system provide long-term protection in response to bacterial or viral infections or immunization. But the level of protection can vary considerably in both duration and magnitude. What is the basis of this variability? Immunological protection depends on both the quality and quantity of memory T and B cells and of the long-lived plasma cells that secrete antibody. The long-term defense provided by memory CD8 T cells depends primarily on two properties. The first is their ability to increase their numbers rapidly and exert potent effector responses—such as the secretion of cytotoxic molecules, and the antiviral cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α)—when antigen is re-encountered. The second is their ability to persist for long periods through homeostatic proliferation, a capacity for self-renewal that maintains the memory CD8 T cell population through a slow, steady cell turnover. Thus, the proliferative response of memory CD8 T cells to both antigen and homeostatic signals determines the quality of immune protection provided by these cells.

Four studies—including papers in this issue by Sun and Bevan (1) on page 339 and Shedlock and Shen (2) on page 337, and reports by Bourgeois et al. (3) and Janssen et al. (4)—reveal that the quality of memory CD8 T cells depends on help from CD4 T cells. The importance of CD4 T cell “help” for generating and shaping B cell and CD8 T cell responses is well documented, but the new papers reveal that although memory CD8 T cells are generated in the absence of CD4 T cells, they display poorer recall responses than memory CD8 T cells generated with CD4 help. CD4 T cell help was examined in both traditional T helper-dependent and T helper-independent systems. The unifying finding is that CD8 T cell proliferation in response to a second encounter with antigen is severely impaired in memory CD8 T cells formed without CD4 help. Furthermore, the ability of the “unhelped” memory CD8 T cells to produce IFN-γ and interleukin-2 (IL-2) and to survive when restimulated is reduced compared with “helped” memory cells (24). CD4 T cell help does not simply determine whether naïve CD8 T cells become activated, but rather appears to provide instructive signals that are incorporated during memory CD8 T cell differentiation, enhancing development of cells with a high proliferative potential. Intriguingly, defects in CD8 T cell responses in the absence of CD4 T cell help are not readily apparent during the early stages of acute viral or bacterial infection. The reason for this is that effector functions, such as IFN-γ production and cytolytic activity, are comparable in the primary effector cells regardless of whether CD4 T cell help is available. It is only later, after formation of the memory CD8 T cell population, that the inferior quality of “unhelped” CD8 T cells can be detected. However, other effector CD8 T cell properties that were not analyzed in these studies also may be affected by the lack of CD4 help (see the figure). Nonetheless, signals from CD4 T cells clearly fine-tune the quality of memory CD8 T cells, which ultimately impacts the quality of immune protection (1, 2).

Quality control of memory CD8 T cells. CD4 T cell “help” is required for a high-quality, protective memory CD8 T cell response. (Top) In the presence of CD4 T cell “help,” activated CD8 T cells clonally expand and develop into cytolytic effector cells (red). The effector cells then progressively differentiate (red to green to blue) into long-lived memory CD8 T cells that have robust recall responses (that is, they can expand rapidly and secrete IFN-γ, TNF-α and IL-2) when restimulated and are maintained by periodic homeostatic proliferation. (Bottom) Without antigen-specific CD4 T cell help, the effector cells develop into memory CD8 T cells that lack superior recall responses (stippled coloring). In CD4-deficient animals, the generation of primary effector cells appears relatively normal (although other functions may be impaired). In this case, the resulting memory CD8 T cell population is usually smaller and formation of memory cell properties is impaired, that is, their ability to clonally expand, survive, and secrete IL-2 and IFN-γ when restimulated is reduced. Also, the number of “unhelped” memory CD8 T cells may gradually decline due to reduced homeostatic proliferation. CD4 T cell help may act both directly on activated CD8 T cells through the CD40 ligand and its receptor, and indirectly by affecting the state of the activated APCs that prime naïve CD8 T cells. CD4 help is necessary early on, but may also influence CD8 T cells and their acquisition of memory cell properties at later stages.

Previous studies examining the formation of memory CD8 T cells in CD4-deficient animals found that memory CD8 T cells were generated during acute viral and bacterial infections in CD4-deficient animals, albeit in smaller numbers (5, 6, 9). These animals were protected against reinfection, indicating that memory CD8 T cell recall responses were intact. It has taken the elegant work of Sun and Bevan (1) and Shedlock and Shen (2), who compared the responses between “helped” and “unhelped” memory CD8 T cells on a cell-by-cell basis and in a physiological setting of infection in vivo, to demonstrate the qualitative effect of CD4 help on memory CD8 T cell responses.

How do CD4 T cells control formation of high-quality memory CD8 T cells? Classically, it has been demonstrated that CD4 T cells provide help by secreting key cytokines (for example, IL-2 and IL-4) that potentiate B cell and CD8 T cell responses. In addition, CD4 T cells deliver stimulatory signals through their CD40L to the CD40 receptor expressed by B cells and antigen-presenting cells (APCs). These signals foster development of B cells into antibody-producing cells and activate APCs, which then efficiently prime naïve CD8 T cells. Moreover, the loss of CD4 T cell function during chronic viral infections can have deleterious consequences on the ability of antigen-specific CD8 T cells to maintain their effector responses (7, 8).

Bourgeois et al. (3) provided evidence for a new model of CD4 T cell help during classic T helper-dependent immune responses. They found that activated CD8 T cells express CD40, which permits them to directly communicate with CD4 T cells, boosting the formation of highly responsive memory CD8 T cells. This model of direct interactions between CD4 and CD8 T cells does not exclude the traditional view that CD4 T cells act indirectly by activating APCs, which, in turn, stimulate CD8 T cell responses. In addition, it is possible that in CD4 T cell-deficient animals, the lack of B cell responses could exacerbate the defective development or maintenance of memory CD8 T cells.

Several reports have characterized the “programmed” differentiation of naïve CD8 T cells into effector and memory T cells (1013). They claim that only a brief period of antigenic stimulation is necessary to cause naïve CD8 T cells to become committed to clonal expansion and differentiate into cytotoxic effector cells that subsequently develop into long-lived protective memory CD8 T cells (1013). Because the blueprint for the CD8 T cell developmental program appears to be generated within a short time period (∼24 hours), one would predict that CD4 T cell influence would be exerted early during the priming of naïve CD8 T cells. Indeed, Janssen et al. (4) have shown that depletion of CD4 T cells 3 days after T helper-dependent immunization did not impair the high proliferative capacity of CD8 T cells, indicating that CD4 T cell signals were incorporated into the developmental program within the first 72 hours of CD8 T cell activation. However, two recent studies highlight a model in which memory CD8 T cell differentiation continues for several weeks after resolution of an acute viral or bacterial infection (14, 15). This model is based on the observation that “hallmark” memory cell qualities—including enhanced proliferation in response to both antigen and homeostatic signals and increased expression of IL-2, bcl-2, and the lymph node homing molecules, L-selectin and CCR7—are gradually acquired by the antigen-specific CD8 T cell population several weeks after infection (1416). Thus, it will be important to more closely analyze whether CD4 help is required at time points beyond naïve CD8 T cell priming to ensure the differentiation of optimal memory CD8 T cells (see the figure). In the absence of antigen-specific CD4 T cells, perhaps the progressive acquisition of a high proliferative capacity toward antigen and homeostatic signals is aborted as memory CD8 T cells develop. It remains to be determined if the “unhelped” memory CD8 T cells respond to homeostatic proliferative signals, but it appears from some studies that memory CD8 T cell numbers gradually decline in mice lacking CD4 T cells, which suggests that their self-renewing capacity is reduced (3, 6, 9). The inability to develop into optimal memory CD8 T cells in the absence of CD4 T cell help could reflect inadequate reprogramming of gene expression patterns during memory CD8 T cell development. Therefore, it will be important to compare the gene expression profiles between “helped” and “unhelped” memory CD8 T cells to better understand how memory CD8 T cell differentiation proceeds.

How “fixed” are memory CD8 T cell qualities? In other words, are the qualities instilled during the initial priming of naïve CD8 T cells permanently embedded, or are they amenable to change every time the T cells are activated? Current data favor the former model, because the presence of CD4 help during “unhelped” memory CD8 T cell recall responses could not remedy their proliferative defects; and vice versa, the lack of CD4 help during “helped” memory CD8 T cell recall responses did not impair their expansion (3, 4). However, these experiments raise two concerns. First, the CD4 help that was supplied to “unhelped” memory CD8 T cells arose from primary effector CD4 T cells, rather than from memory CD4 T cells, and therefore, may not have been robust enough. Second, these studies did not examine whether the secondary memory CD8 T cell population that arose from the “helped” then “unhelped” situation had any qualitative defects. Perhaps, like the primary response, short-lived secondary effector cells are generated normally without CD4 help, but the secondary memory population will be suboptimal. Janssen et al. (4) showed that addition of IL-2 could correct the proliferative defect of the unhelped CD8 T cells in vitro, but this has not been verified in vivo. Furthermore, Bourgeois et al. (3) demonstrated that the memory CD8 T cells generated without CD4 help produced less IL-2. Therefore, one might speculate whether the autocrine production of IL-2 determines optimal memory CD8 T cell proliferative responses. In support of this idea, Wherry et al. (15) show that the subset of memory CD8 T cells that produces IL-2 has greater proliferative responses than the subset that cannot. Together, these findings suggest that the developmental program instilled in the absence of CD4 T cells may lack instructions to produce IL-2 autonomously and that this is an important function for enhanced recall responses.

This interesting group of papers (14) clearly identify that multiple signals, both intrinsic and extrinsic, are integrated into the CD8 T cell developmental program and drive the formation of superior protective responses. Signals from CD4 T cells, perhaps both direct and indirect, help to mold the functional responsiveness of memory CD8 T cells and in particular their ability to acquire a high proliferative potential. It will be imperative to implement this concept into the design of CD8 T cell-oriented vaccines in order to generate the most long-lasting and efficacious CD8 T cell protection possible. Greater clarification of how CD4 help influences memory CD8 T cell responsiveness will also yield important therapeutic insights into diseases such as AIDS, where CD4 T cell help is reduced or obliterated.

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