8536d_ch08_185-199 8/22/02 11: 49 AM Page 188 mac100 mac 100: 128_tm: 8536d: Goldsby et al./ Immunology 5e- 188 PART I1 Generation of B-Cell and T-Cell Response TABLE8-1 Antigen-presenting cells Professional antigen-presenting cells Nonprofessional antigen-presenting cells Dendritic cells(several types) Fibroblasts(skin) Thymic epithelial cells Glial cells(brain) Thyroid epithelial cells Pancreatic beta cells Vascular endothelial cells At about the same time, A. Townsend and his colleagues Macrophages must be activated by phagocytosis of began to identify the proteins of influenza virus that were particulate antigens before they express class II mHC ecognized by Tc cells. Contrary to their expectations, they molecules or the co-stimulatory B7 membrane found that internal proteins of the virus, such as matrix molecule and nucleocapsid proteins, were often recognized by Tc. b cells constitutively express class II MHC molecules but more Moreover, Townsends work revealed that Tc cells recog must be activated before they express the co-stimulatory B7 molecule nized short linear peptide sequences of the influenza pro- tein. In fact, when noninfected target cells were incubated Several other cell types, classified as nonprofessional in vitro with synthetic peptides corresponding to se- antigen-presenting cells, can be induced to express class ll quences of internal influenza proteins, these cells could be MHC molecules or a co-stimulatory signal (Table 8-1) cognized by Tc cells and subsequently lysed just as well Many of these cells function in antigen presentation only as target cells that had been infected with live influenza for short periods of time during a sustained inflammator virus. These findings along with those presented in Figure response 8-3 suggest that antigen processing is a metabolic process Because nearly all nucleated cells express class I MHC that digests proteins into peptides, which can then be dis- molecules, virtually any nucleated cell is able to function played on the cell membrane together with a class I or class target cell presenting endogenous antigens to Tc cells. Most II MHC molecule ften, target cells are cells that have been infected by a virus or some other intracellular microorganism. However, altered Most Cells Can Present Antigen with Class I self-cells such as cancer cells, aging body cells, or allogeneic MHC: Presentation with Class ll mhc cells from a graft can also serve as targets Is Restricted to apcs Since all cells expressing either class I or class lI MHC mole. Evidence for Two Processing les can present peptides to T cells, strictly speaking they all could be designated as antigen-presenting cells. However, by and Presentation Pathways convention,cells that display peptides associated with class I MHC molecules to CD8 Tc cells are referred to as target cells, The immune system uses two different pathways to eliminate cells that display peptides associated with class II MHC mole. intracellular and extracellular antigens. Endogenous anti- les to CD4* tH cells are called antigen-presenting cells gens(those generated within the cell) are processed in the cy- (APCs). This convention is followed throughout this text. rosolic pathway and presented on the membrane with class I A variety of cells can function as antigen-presenting cell MHC molecules; exogenous antigens( those taken up by en Their distinguishing feature is their ability to express class l sented on the membrane with class I mhc molecul MHC molecules and to deliver a co-stimulatory signal. Three cell types are classified as professional antigen-presenting (Figure 8-4) cells: dendritic cells, macrophages, and B lymphocytes. These Experiments carried out by L. A. Morrison and T. J. cells differ from each other in their mechanisms of antigen Braciale provided early evidence that the antigenic peptides uptake, in whether they constitutively express class II MHc presented by class I and class II MHC molecules are derived molecules, and in their co-stimulatory activity: from different processing pathways. These researchers based their experimental protocol on the properties of two clones a Dendritic cells are the most effective of the antigen- of Tc cells, one that recognized influenza hemagglutinin a high level of class II MHC molecules and co-k presenting cells. Because these cells constitutively (HA)associated with a class I MHC molecule, and an atypical Tc line that recognized the same antigen associated stimulatory activity, they can activate naive TH cells with a class II MHC molecule.(In this case, and in sonAt about the same time, A. Townsend and his colleagues began to identify the proteins of influenza virus that were recognized by TC cells. Contrary to their expectations, they found that internal proteins of the virus, such as matrix and nucleocapsid proteins, were often recognized by TC cells better than the more exposed envelope proteins. Moreover, Townsend’s work revealed that TC cells recog￾nized short linear peptide sequences of the influenza pro￾tein. In fact, when noninfected target cells were incubated in vitro with synthetic peptides corresponding to se￾quences of internal influenza proteins, these cells could be recognized by TC cells and subsequently lysed just as well as target cells that had been infected with live influenza virus. These findings along with those presented in Figure 8-3 suggest that antigen processing is a metabolic process that digests proteins into peptides, which can then be dis￾played on the cell membrane together with a class I or class II MHC molecule. Most Cells Can Present Antigen with Class I MHC; Presentation with Class II MHC Is Restricted to APCs Since all cells expressing either class I or class II MHC mole￾cules can present peptides to T cells, strictly speaking they all could be designated as antigen-presenting cells. However, by convention, cells that display peptides associated with class I MHC molecules to CD8 TC cells are referred to as target cells; cells that display peptides associated with class II MHC mole￾cules to CD4 TH cells are called antigen-presenting cells (APCs). This convention is followed throughout this text. A variety of cells can function as antigen-presenting cells. Their distinguishing feature is their ability to express class II MHC molecules and to deliver a co-stimulatory signal. Three cell types are classified as professional antigen-presenting cells: dendritic cells, macrophages, and B lymphocytes. These cells differ from each other in their mechanisms of antigen uptake, in whether they constitutively express class II MHC molecules, and in their co-stimulatory activity: ■ Dendritic cells are the most effective of the antigen￾presenting cells. Because these cells constitutively express a high level of class II MHC molecules and co￾stimulatory activity, they can activate naive TH cells. ■ Macrophages must be activated by phagocytosis of particulate antigens before they express class II MHC molecules or the co-stimulatory B7 membrane molecule. ■ B cells constitutively express class II MHC molecules but must be activated before they express the co-stimulatory B7 molecule. Several other cell types, classified as nonprofessional antigen-presenting cells, can be induced to express class II MHC molecules or a co-stimulatory signal (Table 8-1). Many of these cells function in antigen presentation only for short periods of time during a sustained inflammatory response. Because nearly all nucleated cells express class I MHC molecules, virtually any nucleated cell is able to function as a target cell presenting endogenous antigens to TC cells. Most often, target cells are cells that have been infected by a virus or some other intracellular microorganism. However, altered self-cells such as cancer cells, aging body cells, or allogeneic cells from a graft can also serve as targets. Evidence for Two Processing and Presentation Pathways The immune system uses two different pathways to eliminate intracellular and extracellular antigens. Endogenous anti￾gens (those generated within the cell) are processed in the cy￾tosolic pathway and presented on the membrane with class I MHC molecules; exogenous antigens (those taken up by en￾docytosis) are processed in the endocytic pathway and pre￾sented on the membrane with class II MHC molecules (Figure 8-4). Experiments carried out by L. A. Morrison and T. J. Braciale provided early evidence that the antigenic peptides presented by class I and class II MHC molecules are derived from different processing pathways. These researchers based their experimental protocol on the properties of two clones of TC cells, one that recognized influenza hemagglutinin (HA) associated with a class I MHC molecule, and an atypical TC line that recognized the same antigen associated with a class II MHC molecule. (In this case, and in some 188 PART II Generation of B-Cell and T-Cell Responses TABLE 8-1 Antigen-presenting cells Professional antigen-presenting cells Nonprofessional antigen-presenting cells Dendritic cells (several types) Fibroblasts (skin) Thymic epithelial cells Macrophages Glial cells (brain) Thyroid epithelial cells B cells Pancreatic beta cells Vascular endothelial cells 8536d_ch08_185-199 8/22/02 11:49 AM Page 188 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-: