8536dch102218/29/022:03 PM Page221mac83Mac83:379k T-Cell aturation,chapter 10 Activation and Differentiation HE ATTRIBUTE THAT DISTINGUISHES ANTIGEN recognition by most T cells from recognition by B ells is MHC restriction. In most cases, both the maturation of progenitor T cells in the thymus and the acti 901090 vation of mature T cells in the periphery are influenced by the involvement of MHC molecules. The potential antigeni diversity of the T-cell population is reduced during matura tion by a selection process that allows only MHC-restricted and nonself-reactive T cells to mature. The final stages in the maturation of most T cells proceed along two different de- velopmental pathways, which generate functionally distinct CD4 and CD8* subpopulations that exhibit class II and class I MHC restriction, respectively. Activation of mature peripheral T cells begins with the Engagement of TcR by Peptide: MHC Initiates interaction of the T-cell receptor( TCr)with an antigenic Signal Transduction peptide displayed in the groove of an MHC molecule. Al TCR, its low avidity necessitates the involvement of corecep-. T-Cell Maturation and the Thymus tors and other accessory membrane molecules that strengthen the TCR-antigen- MHC interaction and trans- Thymic Selection of the T-Cell Repertoire duce the activating signal Activation leads to the prolifera- TH-Cell Activation tion and differentiation of t cells into various types of T-Cell Differentiation ffector cells and memory T cells. Because the vast majority of thymocytes and peripheral T cells express the aB T-cell a Cell Death and T-Cell Populations receptor rather than the y8 T-cell receptor, all references to the T-cell receptor in this chapter denote the ap receptor un- Peripheral y8 T-Cells less otherwise indicated. Similarly, unless otherwise indi- cated, all references to T cells denote those aB receptor- bearing T cells that undergo MHC restriction As indicated in Chapter 2, the thymus occupies a central ole in T-cell biology. Aside from being the main source of all Tcells, it is where T cells diversify and then are shaped into effective primary T-cell repertoire by an extraordinary pair of T-Cell Maturation and the thymus selection processes. One of these, positive selection, permits the survival of only those T cells whose TCRs are capable of Progenitor T cells from the early sites of hematopoiesis begin recognizing self-MHC molecules. It is thus responsible for to migrate to the thymus at about day ll of gestation in mice the creation of a self-MHC-restricted repertoire of T cells. and in the eighth or ninth week of gestation in humans. In a The other, negative selection, eliminates T cells that react manner similar to B-cell maturation in the bone marrow, T- too strongly with self-MHC or with self-MHC Plus self- cell maturation involves rearrangements of the germ-line peptides. It is an extremely important factor in generating TCR genes and the expression of various membrane mark- a primary T-cell repertoire that is self-tolerant ers In the thymus, developing T cells, known as thymocytes, As shown in Figure 10-1, when T-cell precursors arrive at proliferate and differentiate along developmental pathways the thymus, they do not express such signature surface mark that generate functionally distinct subpopulations of mature ers of T cells as the T-cell receptor, the CD3 complex, or the T cells coreceptors CD4 and CD8. In fact, these progenitor cells haveAs indicated in Chapter 2, the thymus occupies a central role in T-cell biology. Aside from being the main source of all T cells, it is where T cells diversify and then are shaped into an effective primary T-cell repertoire by an extraordinary pair of selection processes. One of these, positive selection, permits the survival of only those T cells whose TCRs are capable of recognizing self-MHC molecules. It is thus responsible for the creation of a self-MHC-restricted repertoire of T cells. The other, negative selection, eliminates T cells that react too strongly with self-MHC or with self-MHC plus self￾peptides. It is an extremely important factor in generating a primary T-cell repertoire that is self-tolerant. As shown in Figure 10-1, when T-cell precursors arrive at the thymus, they do not express such signature surface mark￾ers of T cells as the T-cell receptor, the CD3 complex, or the coreceptors CD4 and CD8. In fact, these progenitor cells have chapter 10 ■ T-Cell Maturation and the Thymus ■ Thymic Selection of the T-Cell Repertoire ■ TH-Cell Activation ■ T-Cell Differentiation ■ Cell Death and T-Cell Populations ■ Peripheral T-Cells T-Cell Maturation, Activation, and Differentiation T     recognition by most T cells from recognition by B cells is MHC restriction. In most cases, both the maturation of progenitor T cells in the thymus and the acti￾vation of mature T cells in the periphery are influenced by the involvement of MHC molecules. The potential antigenic diversity of the T-cell population is reduced during matura￾tion by a selection process that allows only MHC-restricted and nonself-reactive T cells to mature. The final stages in the maturation of most T cells proceed along two different de￾velopmental pathways, which generate functionally distinct CD4 and CD8 subpopulations that exhibit class II and class I MHC restriction, respectively. Activation of mature peripheral T cells begins with the interaction of the T-cell receptor (TCR) with an antigenic peptide displayed in the groove of an MHC molecule. Al￾though the specificity of this interaction is governed by the TCR, its low avidity necessitates the involvement of corecep￾tors and other accessory membrane molecules that strengthen the TCR-antigen-MHC interaction and trans￾duce the activating signal. Activation leads to the prolifera￾tion and differentiation of T cells into various types of effector cells and memory T cells. Because the vast majority of thymocytes and peripheral T cells express the  T-cell receptor rather than the T-cell receptor, all references to the T-cell receptor in this chapter denote the  receptor un￾less otherwise indicated. Similarly, unless otherwise indi￾cated, all references to T cells denote those  receptor￾bearing T cells that undergo MHC restriction. T-Cell Maturation and the Thymus Progenitor T cells from the early sites of hematopoiesis begin to migrate to the thymus at about day 11 of gestation in mice and in the eighth or ninth week of gestation in humans. In a manner similar to B-cell maturation in the bone marrow, T￾cell maturation involves rearrangements of the germ-line TCR genes and the expression of various membrane mark￾ers. In the thymus, developing T cells, known as thymocytes, proliferate and differentiate along developmental pathways that generate functionally distinct subpopulations of mature T cells. Engagement of TcR by Peptide: MHC Initiates Signal Transduction ζ ζ γδε 8536d_ch10_221 8/29/02 2:03 PM Page 221 mac83 Mac 83:379_kyw: