Effector CTLs Are Generated from CTL Precursors

Naive TC cells are incapable of killing target cells and are therefore referred to as CTL precursors (CTL-Ps) to denote their functionally immature state. Only after a CTL-P has been activated will the cell differentiate into a functional CTL with cytotoxic activity. Generation of CTLs from CTL-Ps appears to require at least three sequential signals (Figure 14-1):

■ An antigen-specific signal 1 transmitted by the TCR complex upon recognition of a peptide-class I MHC molecule complex

■ A co-stimulatory signal transmitted by the CD28-B7 interaction of the CTL-P and the antigen-presenting cell

■ A signal induced by the interaction of IL-2 with the high-affinity IL-2 receptor, resulting in proliferation and differentiation of the antigen-activated CTL-P into effector CTLs

Unactivated CTL-Ps do not express IL-2 or IL-2 receptors, do not proliferate, and do not display cytotoxic activity. Antigen activation induces a CTL-P to begin expressing the IL-2 receptor and to a lesser extent IL-2, the principal cytokine required for proliferation and differentiation of activated CTL-Ps into effector CTLs. In some cases, the amount of IL-2 secreted by an antigen-activated CTL-P may be sufficient to induce its own proliferation and differentiation; this

Class II MHC

Class II MHC

Ctl Th1 Interaction

IL-2R expression -

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IL-2 expression -

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Proliferation -

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Effector cytotoxic -

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function

Generation of effector CTLs. Upon interaction with antigen-class I MHC complexes on appropriate target cells, CTL-Ps begin to express IL-2 receptors (IL-2R) and lesser amounts of IL-2. Proliferation and differentiation of antigen-activated CTL-Ps generally require additional IL-2 secreted by TH1 cells resulting from antigen activation and proliferation of CD4+ T cells. In the subsequent effector phase, CTLs destroy specific target cells.

FIGURE 14-1

Generation of effector CTLs. Upon interaction with antigen-class I MHC complexes on appropriate target cells, CTL-Ps begin to express IL-2 receptors (IL-2R) and lesser amounts of IL-2. Proliferation and differentiation of antigen-activated CTL-Ps generally require additional IL-2 secreted by TH1 cells resulting from antigen activation and proliferation of CD4+ T cells. In the subsequent effector phase, CTLs destroy specific target cells.

is particularly true of memory CTL-Ps, which have lower activation requirements than naive cells do (Figure 14-2a).

In general, though, most activated CTL-Ps require additional IL-2 produced by proliferating TH1 cells to proliferate and differentiate into effector CTLs. The fact that the IL-2 receptor is not expressed until after a CTL-P has been activated by antigen plus a class I MHC molecule favors the clonal expansion and acquisition of cytotoxicity by only the antigen-specific CTL-Ps.

The proliferation and differentiation of both antigen-activated TH1 cells and CTL-Ps depend on IL-2. In IL-2 knockout mice, the absence of IL-2 has been shown to abolish CTL-mediated cytotoxicity. After clearance of antigen, the level of IL-2 declines, which induces TH1 cells and CTLs to undergo programmed cell death by apoptosis. In this way, the immune response is rapidly terminated, lessening the likelihood of nonspecific tissue damage from the inflammatory response.

The role of TH1 cells in the generation of CTLs from naive CTL-Ps is not completely understood, and it is unlikely that a Th1 cell and CTL-P interact directly. However, IL-2 and co-stimulation are important in the transformation of naive CTL-Ps into effector cells, and TH1 cells can be mediators in the provision of these essential requirements. As shown in Figure 14-2b, the interaction of helper cells with antigen-presenting cells can result in production of IL-2 by the TH1 cell. The paracrine action of this cytokine on nearby naive CTL-Ps whose TCRs are engaged can cause them to proliferate and differentiate into active CTLs. Additionally, TH1 can induce the up-regulation of co-stimulatory molecules on the

Memory CTL-P

Memory CTL-P

Th1 Ctl Cell
Virus-infected dendritic cell
Ctl Prolifeation And Activation
-> CTL

Naive CTL-P

Naive CTL-P

Cartoon Bathroom Images
Virus-infected dendritic cell
Generation Effector Ctls
} CTL

FIGURE 14-2

Proliferation of memory CTL-Ps may not require help from Th cells. (a) Antigen-activated memory CTL-Ps appear to secrete sufficient IL-2 to stimulate their own proliferation and differentiation into effector CTLs. They also may not require the CD28-B7 co-stimulatory signal for activation. (b) A TH cell may provide the IL-2 necessary for proliferation of an antigen-activated naive CTL-P when it binds to the same APC as the CTL-P. Also, Th cells may alter the behavior of APCs in a number of ways, such as increasing the display of co-stimulatory molecules by the APC.

surface of antigen-presenting cells. In this manner, TH1 cells help CTL-P division and differentiation by causing the generation of adequate levels of co-stimulation.

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  • mollie
    What is meant by effector CTL precursor CTL?
    8 years ago

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