MHC Class laRestricted Responses

Upon activation, massive clonal expansion of L. monocytogenes epitope-specific CD8+ T cells results in amplification of virtually undetectable levels of naïve cells of a given specificity to levels that are readily detectable (1-2% cells in the spleen) (Busch et al. 1998b). To achieve this expansion, Ag-specific CD8+ T cells exhibit doubling times of 6-8 h/division (Blattman et al. 2002). Although responses to L. monocytogenes are multiclonal, CD8+ T-cell populations specific for independent antigens undergo expansion with coordinate kinetics. Within 7-9 days after infection, the rapidly expanding CD8+ T cells of differing specificities (i.e., LLO91-99, p60217-225) reach their numerical peak in unison (Busch et al. 1998b). This point marks the onset of the death or contraction phase of the response where > 90% of cells specific for each epitope die within 3-5 days and the remaining cells comprise the Ag-specific memory cell pool (see Figure 11.1.). This initial memory cell pool is maintained in number and function for the life of the host (Ku et al. 2000); through homeostatic proliferation mechanisms independent of antigen (Lau et al. 1994; Murali-Krishna et al. 1999; Wong and Pamer 2001; Jabbari and Harty 2005), but dependent on the presence of cytokines, such as IL-15 (Ku et al. 2000).

After L. monocytogenes infection, the exact timing of the transition from the expansion to contraction phase of the CD8+ T-cell response is dependent on the strain of bacteria used; the peak response to virulent L. monocytogenes is slightly delayed (8-9 days p.i.) compared to attenuated strains (day 7 p.i.) (Pope et al. 2001; Badovinac and Harty 2002; Wong and Pamer 2003; Porter and Harty 2006). Using highly sensitive methods of Ag detection ("Direct Ex vivo Antigen Display (DEAD)" and "functional Ag display" assays), it was demonstrated that infection with virulent L. monocytogenes results in delayed peaks in the bacterial load and resultant Ag presentation compared to infection with attenuated (actA-deficient) L. monocytogenes (Wong and Pamer 2003; Porter and Harty 2006). In either case, the peak of functional Ag display was followed ~ 5 days later by the transition from expansion to contraction of CD8+ T-cell numbers. Although the reason for the 5-day interval between peak Ag levels and the onset of CD8+ T-cell contraction is unknown, it is possible that the peak of functional Ag display stimulates the highest relative number of precursors programmed to undergo a set number of divisions resulting in a synchronized peak (expansion to contraction transition). Alternatively, it may be that continued

Figure legend:

Figure legend:

Figure 11.1. MHC Class Ia-restricted CD8+ T cell response to L. monocytogenes. Total number of T cells specific for L. monocytogenes-derived antigens (antigens 1(dashed) and 2 (solid)). The coordinate expansion of Ag-specific CD8+ T cells after infection (1 x) is followed by a rapid and reproducible contraction phase leading to long-lived Ag-specific CD8+ T cell memory. Reexposure to previously lethal doses of L. monocytogenes (10 x) results in a more rapid and robust expansion resulting in Ag-specific CD8+ T cell numbers in marked excess over the peak of the primary response. The responding Ag-specific CD8+ T cells are capable of dramatically limiting bacterial burden. In comparison to primary CD8+ T cell response, the contraction phase of the secondary response is delayed.

Ag interaction from the onset of infection to the peak of functional antigen display can influence the number of divisions achieved by responding CD8+ T cells (Porter and Harty 2006). In this scenario, it is the loss or absence of Ag interaction shortly after peak Ag display that leads to conclusion of the "program" of expansion ~ 5 days later. Finally, both mechanisms may participate in the shaping of the CD8+ T-cell response.

Depending on the type of infection, a relatively diverse responding TCR repertoire will become focused so that cells of the highest affinity comprise the majority of the Ag-specifc cells (Malherbe et al. 2004). In the case of murine listeriosis, the responding T-cell populations have relatively diverse TCR repertoire utilization throughout the primary response into memory (Busch et al. 1998a; Opferman et al. 1999). As will be discussed later, some focusing of the TCR repertoire does occur during the secondary response to L. monocytogenes (Busch et al. 1998a).

Memory T cells are a phenotypically and functionally heterogeneous population and it is unknown when cells with memory characteristics develop during the immune response. In recent years, attempts have been made at identifying memory cell precursors shortly after Ag exposure by virtue of expression of a variety of surface markers found on memory cells. No single marker of "memory cell precursors" has been identified; however, these studies have identified two populations of memory cells defined largely by their tissue distribution (Sallusto et al. 1999; Wherry et al. 2003; Jabbari and Harty 2006). Effector (Tem) and central (TCM) memory populations are defined by their relative expression of low or high levels, respectively, of surface homing molecules, such as CD62L and CCR7, that permit entry into lymph nodes. It has been hypothesized that TEM serve a primary surveillance role based on their increased ability for target-cell killing. TCM may serve the complimentary role as a reservoir of Ag-specific cells poised for expansion after reencountering cognate Ag.

Expression of the IL-7 receptor (CD127) has been investigated as an early marker of memory. IL-7 is a critical cytokine for the survival of T cells, and it has been suggested that expression of its receptor in a small fraction of Ag-specific CD8+ T cells at the peak of expansion may mark the cells that will survive contraction to become memory (Kaech et al. 2003). In support of this, increased CD127 expression is observed in experimental systems where contraction is limited or absent (Badovinac et al. 2004). On the other hand, recent studies utilizing a variety of vaccination models show that Ag-specific cells expressing high levels of CD127 contract normally (Badovinac et al. 2005; Lacombe et al. 2005). Taken together, these studies suggest that CD127 expression is not the defining factor in the identification of cells that will survive contraction to become memory T cells.

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