Once a functional antigen receptor has appeared on the cell surface, the lymphocyte is tested in two ways. Positive selection tests for the potential usefulness of the antigen receptor, whereas negative selection removes self-reactive cells from the lymphocyte repertoire, rendering it tolerant to the antigens of the body. Positive selection is particularly important for T cells, because it ensures that only cells bearing T-cell receptors that can recognize antigen in combination with self MHC molecules will continue to mature. Positive selection also coordinates the choice of co-receptor expression. CD4 becomes expressed by T cells harboring MHC class II-restricted receptors, and CD8 by cells harboring MHC class I-restricted receptors. This ensures the optimal use of these receptors in responses to pathogens. For B cells, positive selection seems to occur at the final transition from immature to mature B cells, which occurs in peripheral lymphoid tissues. Tolerance to self antigens is enforced by negative selection at different stages throughout the development of both B and T cells, and positive selection likewise seems to represent a continuous process.
Fig. 8.33 A summary of the development of human α:β T cells.
The state of the T-cell receptor genes, the expression of some essential intracellular proteins, and the expression of some cell-surface molecules are shown for successive stages of α:β T-cell development. Note that because the T-cell receptor genes do not undergo further changes during antigen-driven development, only the phases during which they are actively undergoing rearrangement in the thymus are indicated. The antigen-dependent phases of CD4 and CD8 cells are depicted separately, and are detailed in Chapter 9.
TERMINALDIFFERENTIATIONTERMINALANTIGENDEPENDENTDIFFERENTIATIONANTIGENDEPENDENTStem cell Early double-negative thymocyte Late double-negative thymocyte Early double-positive thymocyte Late double-positive thymocyte Naive CD4 T cell Memory CD4 T cell Effector CD4 T cell Naive CD8 T cell Memory CD8 T cell Effector CD8 T cell ˜-chain gene rearrangements T cells °-chain gene rearrangements Intra-cellular proteins Surface marker proteinsANTIGENINDEPENDENTpre-T receptor D–J rearranged V–DJ rearranged V–J rearranged Germline Germline CD34? CD2 HSA CD44hi RAG-1 RAG-2 TdT Lck ZAP-70 RAG-1 RAG-2 TdT Lck ZAP-70 RAG-1 RAG-2 Lck ZAP-70 Lck ZAP-70 LKLF Lck ZAP-70 CD25 CD44lo HSA PT˜CD4 CD8 HSA CD4 CD62L CD45RA CD5 CD69 CD4 CD8 HSA CD4 CD45RO CD44 CD4 CD45RO CD44hi Fas FasL (type 1) CD8 CD45RA CD8 CD45RO CD44 FasL Fas CD8 CD44hi TH17: IL-17 TH1: IFN-°TH2: IL-4 IFN-°granzyme perforin Germline Germline T-cell receptor
Questions.
8.1 True or False: B-cell development is not affected in mice that are lacking the cytokine receptor common γ chain (γ-c).
8.2 Fill-in-the-Blanks: B-cell development is regulated by the expression of various transcription factors that enable gene rearrangement and the successful progression into a new developmental stage. For example, during the _________ stage, Rag-1 and Rag-2 expression is induced by __________, which permits the successful D to J rearrangement and then V to DJ rearrangement of the heavy-chain locus. As a consequence, a functional __________ is expressed, and upon signaling, the cell is instructed to perform _________ and progress toward the next developmental step and rearrange the light-chain locus.