320 paRI I Immune Effector mechanisms that have direct cytotoxic activity. These effectors eliminate naive T cells) are able to respond to TCR-mediated signals foreign cells and altered self-cells by mounting a cytotoxic with little, if any co-stimulation. reaction that lyses their target. The various cytotoxic effector The reason for the different activation requirements of cells can be grouped into two general categories: one com- naive and activated t cells is an area of continuing research, prises antigen-specific cytotoxic T lymphocytes( CTls) and but some clues have been found. One is that many popula unspecific cells, such as natural killer(NK) cells and macro- tions of naive and effector T cells express different isoforms phages. The target cells to which these effectors are directed of CD45, designated CD45RA and CD45RO, which are pro include allogeneic cells, malignant cells, virus-infected cells, duced by alternative splicing of the Rna transcript of the and chemically conjugated cells. The other group is a sub- CD45 gene. This membrane molecule mediates TCR signal population of effector CD4* T cells that mediates delayed- transduction by catalyzing dephosphorylation of a tyrosine type hypersensitivity reactions(see Chapter 16). The next residue on the protein tyrosine kinases Lck and Fyn, activat- section reviews the general properties of effector T cells and ing these kinases and triggering the subsequent steps in T-cell how they differ from naive T cells. activation(see figures 10-10 and 10-11). The CD45RO iso- form, which is expressed on effector T cells, associates with the TCR complex and its coreceptors, CD4 and CD8, much General Properties of Effector T Cells better than does the CD45RA isoform, which is expressed by naive T cells. Memory T cells have both isoforms, but the The three types of effectorTcells-CD4*, THl and TH2 cells, CD45RO is predominant. As a result, effector and memory and CD8* CTLs-exhibit several properties that set them T cells are more sensitive to TCR-mediated activation by a art from naive helper and cytotoxic T cells (Table 14-1). In peptide-MHC complex. They also have less stringent re particular, effector cells are characterized by their less strin quirements for co-stimulatory signals and therefore are able gent activation requirements, increased expression of cell- to respond to peptide -MHC complexes displayed on target adhesion molecules, and production of both membrane- cells or antigen-presenting cells that lack the co-stimulatory bound and soluble effector molecules B7 molecules The Activation Requirements Cell-Adhesion molecules facilitate of t cells differ TCR-Mediated Interactions T cells at different stages of differentiation may respond with CD2 and the integrin LFA-1 are cell-adhesion molecules on different efficiencies to signals mediated by the T-cell recep- the surfaces of T cells that bind, respectively, to LFA-3 and tor and may consequently require different levels of a second ICAMs(intracellular cell-adhesion molecules) on antigen set of co-stimulatory signals. As described in Chapter 10, presenting cells and various target cells(see Figure 9-13). The activation of naive T cells and their subsequent proliferation level of LFA-1 and CD2 is twofold to fourfold higher on and differentiation into effector T cells require both a pri- effector T cells than on naive T cells, enabling the effector mary signal, delivered when the TCR complex and CD4 T cells to bind more effectively to antigen-presenting cells or CD8 coreceptor interact with a foreign peptide-MHc and to various target cells that express low levels of ICAMs molecule complex, and a co-stimulatory signal, delivered by LFA-3 nteraction between particular membrane molecules on the As Chapter 9 showed, the initial interaction of an effector T cell and the antigen-presenting cell. In contrast, antigen T cell with an antigen-presenting cell or target cell is weak, experienced effector cells and memory cells(as opposed to allowing the TCr to scan the membrane for specific peptides TABLE 14-1 Comparison of naive and effector T cells Property Naive t cells Effector T cells stimulatory signal (CD28-B7 interaction) Required for activation equired for activation CD45RA CD45RO Cell-adhesion molecules(CD2 and LFA-1) fficking patterns HEVs' in secondary lymphoid tissue Tertiary lymphoid tissue inflammatory sites HEV= high endothelial venules, sites in blood vessel used by lymphocytes for extravasationthat have direct cytotoxic activity. These effectors eliminate foreign cells and altered self-cells by mounting a cytotoxic reaction that lyses their target. The various cytotoxic effector cells can be grouped into two general categories: one com￾prises antigen-specific cytotoxic T lymphocytes (CTLs) and nonspecific cells, such as natural killer (NK) cells and macro￾phages. The target cells to which these effectors are directed include allogeneic cells, malignant cells, virus-infected cells, and chemically conjugated cells. The other group is a sub￾population of effector CD4+ T cells that mediates delayed￾type hypersensitivity reactions (see Chapter 16). The next section reviews the general properties of effector T cells and how they differ from naive T cells. General Properties of Effector T Cells The three types of effector T cells—CD4+ , TH1 and TH2 cells, and CD8+ CTLs—exhibit several properties that set them apart from naive helper and cytotoxic T cells (Table 14-1). In particular, effector cells are characterized by their less strin￾gent activation requirements, increased expression of cell￾adhesion molecules, and production of both membrane￾bound and soluble effector molecules. The Activation Requirements of T Cells Differ T cells at different stages of differentiation may respond with different efficiencies to signals mediated by the T-cell recep￾tor and may consequently require different levels of a second set of co-stimulatory signals. As described in Chapter 10, activation of naive T cells and their subsequent proliferation and differentiation into effector T cells require both a pri￾mary signal, delivered when the TCR complex and CD4 or CD8 coreceptor interact with a foreign peptide–MHC molecule complex, and a co-stimulatory signal, delivered by interaction between particular membrane molecules on the T cell and the antigen-presenting cell. In contrast, antigen￾experienced effector cells and memory cells (as opposed to naive T cells) are able to respond to TCR-mediated signals with little, if any co-stimulation. The reason for the different activation requirements of naive and activated T cells is an area of continuing research, but some clues have been found. One is that many popula￾tions of naive and effector T cells express different isoforms of CD45, designated CD45RA and CD45RO, which are pro￾duced by alternative splicing of the RNA transcript of the CD45 gene. This membrane molecule mediates TCR signal transduction by catalyzing dephosphorylation of a tyrosine residue on the protein tyrosine kinases Lck and Fyn, activat￾ing these kinases and triggering the subsequent steps in T-cell activation (see figures 10-10 and 10-11). The CD45RO iso￾form, which is expressed on effector T cells, associates with the TCR complex and its coreceptors, CD4 and CD8, much better than does the CD45RA isoform, which is expressed by naive T cells. Memory T cells have both isoforms, but the CD45RO is predominant. As a result, effector and memory T cells are more sensitive to TCR-mediated activation by a peptide-MHC complex. They also have less stringent re￾quirements for co-stimulatory signals and therefore are able to respond to peptide-MHC complexes displayed on target cells or antigen-presenting cells that lack the co-stimulatory B7 molecules. Cell-Adhesion Molecules Facilitate TCR-Mediated Interactions CD2 and the integrin LFA-1 are cell-adhesion molecules on the surfaces of T cells that bind, respectively, to LFA-3 and ICAMs (intracellular cell-adhesion molecules) on antigen￾presenting cells and various target cells (see Figure 9-13). The level of LFA-1 and CD2 is twofold to fourfold higher on effector T cells than on naive T cells, enabling the effector T cells to bind more effectively to antigen-presenting cells and to various target cells that express low levels of ICAMs or LFA-3. As Chapter 9 showed, the initial interaction of an effector T cell with an antigen-presenting cell or target cell is weak, allowing the TCR to scan the membrane for specific peptides 320 PART III Immune Effector Mechanisms TABLE 14-1 Comparison of naive and effector T cells Property Naive T cells Effector T cells Co-stimulatory signal (CD28-B7 interaction) Required for activation Not required for activation CD45 isoform CD45RA CD45RO Cell-adhesion molecules (CD2 and LFA-1) Low High Trafficking patterns HEVs* in secondary lymphoid tissue Tertiary lymphoid tissues; inflammatory sites *HEV = high endothelial venules, sites in blood vessel used by lymphocytes for extravasation