Cells at the end stage of differentiation, such as plasmacells, may become so specialized that they lose surfacemolecules such as MHC class II, and are unable torespond to regulatory signals or to proliferate.

The fate of lymphocytes responding to antigen isvaried: some can persist for a long time as memory cells the

life span of memory cells can be more than 40 years inhumans, as judged by the chromosome abnormalities(e.g. cross-linking of DNA which would preventmitosis) found in the blood cells of Hiroshimasurvivors;

other lymphocytes have a short life span, whichexplains why moderate antigenic stimulation does notlead to lymphoid enlargement this is neverthelesssufficient for generating effective cell-mediated andantibody responses.

Apoptosis is critically important for disposing of unwantedcells after an immune response.

The immune system responds to clues thatan infection has taken place beforeresponding strongly to antigensIn recent years it has become appreciated that APCs mustrespond appropriately to an infection, for example, butnot to high levels of harmless substances that mayfluctuate in the environment.

APC activation is generally a response to infection, orat least the presence of substances, such as constituents ofbacterial cell walls, characteristic of infection. Thisrequirement neatly explains the need for adjuvants, whichare typically derived from bacterial components.

Adjuvants are generally necessary in vaccines to stim-ulate a robust immune response. The concept of immuneactivation only in response to infection (or adjuvant as asurrogate for infection), and not to other antigens, hasbeen popularized as the danger hypothesis. This ideaproposes that the immune system does not merelydistinguish self from non-self, but responds to clues thatan infection has taken place before responding strongly toantigens.

In other words, foreign substances may be innocuous orinvisible to the immune system unless accompanied bydanger signals, such as infection. These danger signals areprovided by receptors for microbial products on APCs,such as the Toll-like receptors (TLRs, see Fig. 6.24).

FURTHER READINGAckerman, AL, Cresswell P. Cellular mechanisms governing

cross-presentation of exogenous antigens. Nat Immunol2004;5:678684.

Alberola IJ, Takaki S, Kerner JD, Perlmutter RM. Differentialsignaling by lymphocyte antigen receptors. Annu Rev Immunol1997;15:125154.

Bell D, Young JW, Banchereau J. Dendritic cells. Annu Rev Immunol1999;17:255305.

Boes M, Ploegh HL. Translating cell biology in vitro to immunity invivo. Nature 2004;430:264271.

Brocke P, Garbi N, Momburg F, Hammerling GJ. HLA-DM, HLA-DO and tapasin: functional similarities and differences. CurrOpin Immunol 2002;14:2229.

Clements JL, Boerth NJ, Ran Lee J, Koretzky GA. Integration of Tcell receptor-dependent signaling pathways by adapter proteins.Annu Rev Immunol 1999;17:89108.

Germain RN, Stefanova I. The dynamics of T cell receptor signaling:complex orchestration and the key roles of tempo andcooperation. Annu Rev Immunol 1999;17:467522.

Grakoui A, Bromley SK, Sumen C, et al. The immunologicalsynapse: a molecular machine controlling T cell activation.Science 1999;285:221227.

Healy JI, Goodnow CC. Positive versus negative signaling by lym-phocyte antigen receptors. Annu Rev Immunol 1998;16:645670.

Kloetzel PM. Generation of MHC class I antigens: functionalinterplay between proteasomes and TPPII. Nat Immunol2004;5:661669.

Lehner PJ, Cresswell P. Recent developments in MHC class I-mediated antigen presentation. Curr Opin Immunol 2004;16:8289.

Lehner PJ, Trowsdale J. Antigen processing: coming out gracefully.Curr Biol 1998;8:R605R608.

Mellman I, Turley SJ, Steinman RM. Antigen processing foramateurs and professionals. Trends Cell Biol 1998;8:231237.

Nelson CA, Fremont DH. Structural principles of MHC class IIantigen presentation. Rev Immunogenet 1999;1:4759.

Pamer E, Cresswell P. Mechanisms of MHC class I-restricted antigenprocessing. Annu Rev Immunol 1998;16:323358.

Parham P. Accessory molecules in the immune response. ImmunolRev 1996;153.

FURTHER READING

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Expression of the high-affinity IL-2 receptor on T cells

Fig. 7.23 The high-affinity IL-2R consists of three polypeptidechains, shown schematically. Resting T cells do not express the chain, but after activation they may express up to 50 000 chains per cell. Some of these associate with the chain toform the high-affinity IL-2R.

approximate numbersper cell

at rest

maximum activation

50000

~5000

500

500050 000

! chain" chain # chain

55 kDa 64 kDa75 kDa

"# affinity10$10 M

"#!affinity10$11 M# affinity

very lowin isolation

" affinity10$8 M

#" !

IL-2