Activated T Cells Generate Effector and Memory T Cells

If a naive T cell recognizes an antigen-MHC complex on an appropriate antigen-presenting cell or target cell, it will be activated, initiating a primary response. About 48 hours after activation, the naive T cell enlarges into a blast cell and begins undergoing repeated rounds of cell division. As described earlier, activation depends on a signal induced by engagement of the TCR complex and a co-stimulatory signal induced by the CD28-B7 interaction (see Figure 10-13). These signals trigger entry of the T cell into the G1 phase of the cell

Th cell

Endogenous superantigen is membrane-bound

Th cell

Endogenous superantigen is membrane-bound

Superantigen

Seb Superantigen

Peptide for which TCR is not specific

Class II MHC

Superantigen-mediated crosslinkage of T-cell receptor and class II MHC molecules. A superantigen binds to all TCRs bearing a particular Vp sequence regardless of their antigenic specificity. Exogenous superantigens are soluble secreted bacterial proteins, including various exotoxins. Endogenous superantigens are membrane-embedded proteins produced by certain viruses; they include Mls antigens encoded by mouse mammary tumor virus.

Superantigen

Peptide for which TCR is not specific

Class II MHC

FIGURE 10-16

Superantigen-mediated crosslinkage of T-cell receptor and class II MHC molecules. A superantigen binds to all TCRs bearing a particular Vp sequence regardless of their antigenic specificity. Exogenous superantigens are soluble secreted bacterial proteins, including various exotoxins. Endogenous superantigens are membrane-embedded proteins produced by certain viruses; they include Mls antigens encoded by mouse mammary tumor virus.

cycle and, at the same time, induce transcription of the gene for IL-2 and the a chain of the high-affinity IL-2 receptor. In addition, the co-stimulatory signal increases the half-life of the IL-2 mRNA. The increase in IL-2 transcription, together with stabilization of the IL-2 mRNA, increases IL-2 produc tion by 100-fold in the activated T cell. Secretion of IL-2 and its subsequent binding to the high-affinity IL-2 receptor induces the activated naive T cell to proliferate and differentiate (Figure 10-17). T cells activated in this way divide 2-3 times per day for 4-5 days, generating a large clone of progeny cells, which differentiate into memory or effector T-cell populations.

The various effector T cells carry out specialized functions such as cytokine secretion and B-cell help (activated CD4+ TH cells) and cytotoxic killing activity (CD8+ CTLs). The generation and activity of CTL cells are described in detail in Chapter 14. Effector cells are derived from both naive and memory cells after antigen activation. Effector cells are short-lived cells, whose life spans range from a few days to a few weeks. The effector and naive populations express different cell-membrane molecules, which contribute to different recirculation patterns.

As described in more detail in Chapter 12, CD4+ effector T cells form two subpopulations distinguished by the different panels of cytokines they secrete. One population, called the Th1 subset, secretes IL-2, IFN-7, and TNF-p. The TH1 subset is responsible for classic cell-mediated functions, such as delayed-type hypersensitivity and the activation of cytotoxic T lymphocytes. The other subset, called the TH2 subset, secretes IL-4, IL-5, IL-6, and IL-10. This subset functions more effectively as a helper for B-cell activation.

The memory T-cell population is derived from both naive T cells and from effector cells after they have encountered antigen. Memory T cells are antigen-generated, generally

TABLE 10-3 Exogenous superantigens and their Vß specificity

SPECIFICITY

Superantigen

Disease*

Mouse

Human

Staphylococcal enterotoxins

SEA

Food poisoning

1, 3, 10, 11, 12, 17

nd

SEB

Food poisoning

3, 8.1, 8.2, 8.3

3, 12, 14, 15, 17, 20

SEC1

Food poisoning

7, 8.2, 8.3, 11

12

SEC2

Food poisoning

8.2, 10

12, 13, 14, 15, 17, 20

SEC3

Food poisoning

7, 8.2

5, 12

SED

Food poisoning

3, 7, 8.3, 11 , 17

5, 12

SEE

Food poisoning

11, 15, 17

5.1 , 6.1 -6.3, 8, 18

Toxic-shock-syndrome toxin (TSST1)

Toxic-shock syndrome

15, 16

2

Exfoliative-dermatitis toxin (ExFT)

Scalded-skin syndrome

10, 11, 15

2

Mycoplasma-arthritidis supernatant (MAS)

Arthritis, shock

6, 8.1-8.3

nd

Streptococcal pyrogenic exotoxins (SPE-A, B, C, D)

Rheumatic fever, shock

nd

nd

'Disease results from infection by bacteria that produce

the indicated superantigens.

Normal APC

IL-2

Normal APC

IL-2 gene IL-2R gene

CD28 B7

IL-2 gene IL-2R gene

CD28 B7

Activation

IL-2

IL-2 receptor

Activation

IL-2

IL-2 receptor

Several divisions

Population of memory and effector cells

FIGURE 10-17

Activation of a TH cell by both signal 1 and co-stimulatory signal 2 up-regulates expression of IL-2 and the high-affinity IL-2 receptor, leading to the entry of the T cell into the cell cycle and several rounds of proliferation. Some of the cells differentiate into effector cells, others into memory cells.

Population of memory and effector cells

FIGURE 10-17

Activation of a TH cell by both signal 1 and co-stimulatory signal 2 up-regulates expression of IL-2 and the high-affinity IL-2 receptor, leading to the entry of the T cell into the cell cycle and several rounds of proliferation. Some of the cells differentiate into effector cells, others into memory cells.

long-lived, quiescent cells that respond with heightened reactivity to a subsequent challenge with the same antigen, generating a secondary response. An expanded population of memory T cells appears to remain long after the population of effector T cells has declined. In general, memory T cells express many of the same cell-surface markers as effector T cells; no cell-surface markers definitively identify them as memory cells.

Like naive T cells, most memory T cells are resting cells in the G0 stage of the cell cycle, but they appear to have less stringent requirements for activation than naive T cells do. For example, naive TH cells are activated only by dendritic cells, whereas memory TH cells can be activated by macrophages, dendritic cells, and B cells. It is thought that the expression of high levels of numerous adhesion molecules by memory TH cells enables these cells to adhere to a broad spectrum of antigen-presenting cells. Memory cells also display recirculation patterns that differ from those of naive or effector T cells.

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