Technical Comments

Mechanisms Underlying Antigen-Specific CD8+ T Cell Homeostasis

Science  27 Apr 2001:
Vol. 292, Issue 5517, pp. 595a
DOI: 10.1126/science.292.5517.595a

Badovinac et al. (1) reported important new insights concerning the role of perforin and interferon-γ (IFN-γ) in regulating antigen-specific (Ag-specific) CD8+ T cell homeostasis. Using an attenuated strain ofListeria monocytogenes, they demonstrated that absence of perforin resulted in increased levels of specific CD8+ T cells, whereas absence of IFN-γ contributed to altered immunodominance hierarchies and to a reduced death phase of the CD8+ T cell population following acute infection. Based on these experimental results, it was argued that regulation of specific CD8+ T cell homeostasis by perforin and IFN-γ is brought about by a mechanism that is independent of the role of these effectors for controlling the infection.

Because these dynamics are highly multifactorial and nonlinear, mathematical models are required to precisely investigate this issue. Presented here is such a model (Fig. 1) describing the dynamics between an intracellular pathogen and a specific CD8+ T cell response. The model, which is based on previously published approaches (2–4), takes into account CD8+ T cell clones directed against different epitopes of the pathogen population. The rate of generation and expansion of the CD8+ T cell responses is proportional to antigen load. In the absence of antigen, memory CD8+ T cells decay at a defined rate, which is thought to be low. The model assumes that CD8+ T cells lyse infected cells and secrete soluble mediators, such as IFN-γ, that enhance immunity and interfere with viral replication (5).

Figure 1

CD8+ T cell dynamics in perforin-deficient (PKO) and IFN-γ deficient (GKO) hosts, as predicted by the mathematical model (5). Absence of perforin results in a higher level of specific CD8+ T cells, but not in an altered death phase or immunodominance. Absence of IFN-γ does result in a reduced death phase of the CD8+ cells and in altered immunodominance. Immunodominance hierarchies are shown at equilibrium to keep the graphs clear and concise; however, the immunodominance hierarchies in the model are already established right at the beginning of the infectious process when cytolytic T lymphocyte (CTL) responses start to expand (10).

The outcome of the model is determined by the efficacy of the immune system. Because the model is deterministic, reduction of pathogen load to zero is not possible in the context of the model. If the immune response is efficient, however, pathogen load can be reduced to extremely low values that, in practical terms, correspond to elimination of the pathogen (reduction of load below one bacterial cell or one virus particle). If the immune response is less efficient, pathogen load attains higher values, corresponding to persistent replication.

In the present context, three immune system parameters are important for interpreting the experimental data (Fig. 1): (i) c, the rate of antigen-driven CD8+ T cell proliferation; (ii)p, the rate of CD8+ T cell–mediated lysis of infected cells; and (iii) q, the rate of nonlytic CD8+ T cell–mediated inhibition of microbial replication (e.g., by IFN-γ). Under the model, the level of specific CD8+ T cells is mainly determined by the rates of lytic and nonlytic pathogen inhibition. Weaker inhibition results in higher pathogen load and a higher level of CD8+ T cells (Fig. 1). Unless CD8+ T cell proliferation saturates at low densities, the model predicts that the elevation of CD8+ T cells is significantly higher than the elevation of pathogen load (not shown in Fig. 1), as observed in the experiments of Badovinac et al. (1).

On the other hand, theory suggests that the immunodominance hierarchy of the specific CD8+ T cell clones is governed by competition for antigenic stimulation. This is determined by the magnitude of antigen-driven CD8+ T cell proliferation (6). The more efficient the rate of antigen-driven expansion of a given CD8+ T cell clone, the better its competitive ability, because less antigen is needed for stimulation (7, 8). Because IFN-γ can influence the rate of CD8+ T cell proliferation (through regulation of antigen presentation), a reduction of IFN-γ can result both in higher pathogen load and in shifted immunodominance (Fig. 1).

Because absence of IFN-γ can also result in a higher rate of microbial replication, the model presented here further predicts a reduced death phase of the CD8+ T cell response due to prolonged antigen persistence, even if the pathogen becomes undetectable. With fast microbial replication, the CD8+ T cell response initially reduces pathogen load to low levels; a prolonged phase of limited replication then follows before equilibrium is reached. This interpretation is supported by recent data from mice deficient in IFN-γ that were infected with a strain of lymphocytic choriomeningitis virus (LCMV Armstrong): Compared with wild-type mice, the knockout animals were characterized not only by higher levels of CD8+ T cells in the memory phase, but also by increased and persistent viral load that remained low and nonpathogenic, albeit in this case above the limit of detection (9).

In summary, this brief analysis shows that, contrary to the arguments of Badovinac et al. (1), their main observations can indeed be explained by the basic mechanisms by which perforin and IFN-γ control infection. Of course, mathematical modeling does not preclude the existence of additional and more complicated regulatory effects of these molecules. When interpreting experimental data, however, it is important to keep in mind the most parsimonious mechanism that can lead to the observed results.


Response: The utility of mathematical models to explain complex biological processes is related to how well their assumptions fit the in vivo situation and whether they accurately encompass actual experimental findings. The model of Wodarz is based on three assumptions: (i) increased CD8+ T cell responses in perforin-deficient (PKO) mice result from delayed clearance of infection; (ii) persistent infection accounts for aberrant CD8+ T cell decline in IFN-γ–deficient (GKO) mice; and (iii) persistent infection accounts for altered hierarchies of immunodominance in GKO mice by eliminating competition for antigen.

In contrast to these assumptions, our results show that clearance of attenuated Listeria is identical at early and late times after infection of wild-type and PKO mice. Moreover, immunization of PKO mice with peptide-coated dendritic cells also resulted in increased CD8+ T cell response. By 10 days after infection, clearance of the attenuated Listeria infection (less than 100 bacteria, or less than one infected cell per gram of liver) occurred in both GKO and wild-type mice (1). In subsequent studies, we have found that the response to another subdominant epitope fromListeria is not elevated in GKO mice (2), a result that is not consistent with the generalized increase in subdominant responses predicted by the Wodarz model based on persistent infection and antigen competition.

The Wodarz model also relies on the assumption that persistent infection (y > 0) is required for survival of memory T cells, a contention that is clearly not supported by experimental results (3–5). Thus, the Wodarz model is of limited utility because of assumptions that are not consistent with the data and because of its failure to account for the observed results.

*Also Department of Mathematics, University of Iowa.


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