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 infection with Listeria monocytogenes consists of expansion, contraction, and memory phases. The transition between expansion and contraction is reported to occur on different days postinfection with virulent (8 to 9 days) and attenuated (DeltaactA) (7 days) L. monocytogenes strains. We hypothesized that differences in the infectious courses, and therefore antigen (Ag) display, determine the precise time of the expansion/contraction transition in response to these infections. To test this, we infected BALB/c mice with 0.1 50% lethal dose of DeltaactA or virulent L. monocytogenes and measured bacterial numbers, Ag display, and Ag-specific CD8+-T-cell responses on various days after infection. We found that bacterial numbers and Ag display peaked between 12 and 36 h and between 36 and 60 h after infection with DeltaactA and virulent L. monocytogenes strains, respectively. Infection with DeltaactA L. monocytogenes resulted in a sharp peak in the Ag-specific CD8+-T-cell response on day 7, while infection with virulent L. monocytogenes yielded a prolonged peak with equivalent numbers of Ag-specific CD8+ T cells on days 6, 7, and 8 after infection. Truncating virulent infection with antibiotics on day 1 or 2 after infection resulted in a shift in the expansion/contraction transition from day 8 to day 7 after infection. However, antibiotic treatment beginning on day 3, after the peak of virulent L. monocytogenes infection and Ag display, had no effect upon the magnitude or timing of the CD8+-T-cell response. These results demonstrate a direct relationship between the course of infection and Ag display and that the timing of these events is important in shaping the T-cell response to infection.

CD8+ T cell contraction is controlled by early inflammation.

Pathogen-specific CD8(+) T cells expand in number after infection and then their numbers invariably contract by 90-95%, leaving a stable memory cell pool. The chief features of this response are programmed early after infection; however, the factors regulating contraction are mostly undefined. Here we show that antibiotic treatment before Listeria monocytogenes infection induced numbers of protective memory CD8(+) T cells similar to those in control infected mice, by a pathway without contraction. The absence of contraction correlated with decreased early inflammation and interferon-gamma production and an increased fraction of CD8(+) T cells expressing the interleukin 7 receptor at the peak of the response. Thus, contraction is controlled by early inflammation but is not essential for the generation of protective memory CD8(+) T cells after infection.

MHC class Ia-restricted memory T cells inhibit expansion of a nonprotective MHC class Ib (H2-M3)-restricted memory response.

Listeria monocytogenes infection generates major histocompatibility complex (MHC) class Ia-restricted and MHC class Ib-(H2-M3)-restricted effector and memory CD8+ T cells. However, only MHC class Ia-restricted memory cells expand after rechallenge, and it is unknown if MHC class Ib-restricted memory CD8+ T cells generated by vaccination are protective. We show here that H2-M3-restricted memory CD8+ T cells were capable of secondary expansion but, in contrast to primary H2-M3-restricted effector cells, failed to provide protective immunity. In lm-immune mice, MHC class Ia-restricted memory CD8+ T cells prevented the expansion of H2-M3-restricted memory T cell populations by limiting dendritic cell antigen presentation. Thus, protective immunity by H2-M3-restricted T cells is limited to primary infection, indicating that memory MHC class Ia-restricted T cells prevent nonessential immune responses during secondary infection.

Programmed contraction of CD8(+) T cells after infection.

The extent of infection and rate of pathogen clearance are thought to determine both the magnitude of antigen-specific CD8(+) T cell expansion and the ensuing contraction to a stable number of memory cells. We show that CD8(+) T cell expansion after Listeria monocytogenes infection was primarily dependent on the initial infection dose or amount of antigen displayed, and was also influenced by the rate of pathogen clearance. However, the onset and kinetics of CD8(+) T cell contraction after L. monocytogenes and lymphocytic choriomeningitis virus infections were independent of the magnitude of expansion, dose and duration of infection or amount of antigen displayed. Thus, major features of antigen-specific CD8(+) T cell homeostasis, including the contraction phase of an immune response, may be programmed early after infection.