The Onset of CD8+-T-Cell Contraction Is Influenced by the Peak of Listeria monocytogenes Infection and Antigen Display

The CD8+-T-cell response to bacterial and viral pathogens is important in clearing infections and establishing long-term immunity. In order to initiate a CD8+-T-cell response after acute infection, dendritic cells (DC) must process and present pathogen-derived antigen (Ag) in the context of major histocompatibility complex class I and costimulatory molecules to naive CD8+ T cells (22, 26). The Ag-specific CD8+ T cells are thereby activated to massively expand in number, differentiate into effector cells, and disseminate throughout the body (12, 33). Anywhere from 5 to 10 days after acute infection, the number of Ag-specific T cells reaches a peak and then begins to contract to stable memory levels (11, 12, 15, 19, 33, 37, 38). The pattern of the CD8+-T-cell response to infection (expansion in numbers followed by contraction to stable memory levels) is very consistent within a number of acute infections of mice, including lymphocytic choriomeningitis virus (LCMV), Listeria monocytogenes, herpes simplex virus type 1, Plasmodium yoelii, and influenza virus infections (1, 11, 12, 15, 19, 33, 37, 38). After contraction, the resulting number of memory CD8+ T cells generally represents 5 to 10% of the T-cell numbers at the peak of expansion (1). This numerical relationship between the magnitude of expansion and the number of memory cells is important because the number of memory cells determines the level of protection from subsequent infections (2, 40). It is not yet known what regulates the onset of this precisely controlled death of effector T cells. More is known about the combination of factors that determine the magnitude of CD8+-T-cell expansion. These factors are thought to include the number of available naive Ag-specific precursors, the number of precursors that are recruited, the number of divisions, the amount of antigen produced by the organism, the level of Ag presentation by DC, the infectious dose, and the duration of infection (4, 8, 18, 21, 30, 39, 48, 49, 53). A multitude of recent studies highlight the notion that CD8+-T-cell expansion is largely regulated at a very early stage of T-cell activation. For instance, only 2 to 2.5 h of antigenic stimulation in vitro was required to initiate a series of divisions in naive CD8+ T cells, and 24 h of stimulation could support differentiation of naive Ag-specific T cells into effector and memory cells (23, 43, 51). In vivo, abbreviating the course of bacterial infections with antibiotics had little influence upon the pattern of a CD8+-T-cell response or the generation of memory (4). For instance, when mice were infected with virulent or attenuated (ΔactA) Listeria monocytogenes and treated with antibiotics 24 h after infection, the magnitude of CD8+-T-cell expansion was robust and decreased by only two- to fivefold compared to mice that did not receive antibiotics (4, 13, 32). A similarly modest reduction in the magnitude of the CD8+-T-cell response was found in mice that received an abbreviated infection with herpes simplex virus type 1 (39). Thus, Ag-dependent programming of T-cell expansion and differentiation into effector and memory cells can occur in a short period of time; however, full T-cell expansion appears to require longer infection periods. The data suggest that the programming model of CD8+-T-cell expansion also applies to the contraction phase of the CD8+-T-cell response. Antibiotic treatment of mice 24 h after infection with ΔactA L. monocytogenes resulted in timing and magnitude of CD8+-T-cell contraction similar to those in mice that received ΔactA L. monocytogenes without antibiotic treatment (4, 5). In addition, Ag-specific CD8+ T cells in wild-type mice chronically infected with LCMV clone 13 and perforin knockout mice chronically infected with LCMV Armstrong underwent a normal initial contraction phase (4, 31, 42, 46). These experiments suggested that the timing of T-cell contraction could be separated from the timing of infection clearance and Ag withdrawal. However, while ΔactA L. monocytogenes yielded a CD8+-T-cell response that reproducibly peaked 7 days postinfection regardless of the dose or infection duration (4, 5), multiple laboratories found that the CD8+-T-cell response (to the same Ag) peaks between 8 and 9 days postinfection with 0.1 50% lethal dose (LD50) of virulent L. monocytogenes (10, 13, 24, 32, 37). One difference between virulent and ΔactA L. monocytogenes infections is the time course of infection (14, 16, 29, 34, 52). Thus, we hypothesized that these differences in infection kinetics lead to differences in Ag presentation and the timing of CD8+-T-cell contraction. Experimental support for this hypothesis could affect the T-cell programming model by demonstrating a relationship between the timing of Ag presentation and CD8+-T-cell contraction. In this report, we demonstrate that virulent L. monocytogenes infection results in delayed peaks in the bacterial load and Ag presentation compared to infection with ΔactA L. monocytogenes. In turn, these differences are associated with a prolonged transition between Ag-specific CD8+-T-cell expansion and contraction after virulent L. monocytogenes infection compared to ΔactA L. monocytogenes infection. We also demonstrate that abbreviating virulent L. monocytogenes infection with antibiotics on day 1 or 2 after infection decreases the magnitude of the CD8+-T-cell response and shifts the onset of T-cell contraction to an earlier time. However, antibiotic treatment on day 3 has no measurable influence upon the magnitude and timing of the CD8+-T-cell response. Thus, on a population basis, the onset of the CD8+-T-cell contraction program is influenced by the peak of infection and Ag presentation.