PART II Generation of B-Cell and T-Cell Responses chain of pre-Bc Duj PRO-B CELL PRE-B CELL MMATURE B CELL NAIVE B CELL MATURE B CELL STEM CELL H-chain ge Germ line l VHDHJH L-chain genes VLJL Vpre-B andλ5 Vpre- B andλ5 Germ-line Germ-line RAG-1/2 Membrane ig avy cha u+8 ht chain light chain Pu. 1. Ikaros BSAP(Pax-5) factors others E2A Kit arkers CDI9 CD43 CD25 FIGURE11-3 Sequence of events and characteristics of the stages thesis of both membrane- bound igM and lgD by mature B cells in B-cell maturation in the bone marrow. The pre-B cell expresses a RAG-1/2=two enzymes encoded by recombination-activating genes membrane immunoglobulin consisting of a heavy(H)chain and sur- TdT terminal deoxyribonucleotidyl transferase. A number of B-cell- rogate light chains, Vpre-B and A5. Changes in the RNA processing associated transcription factors are important at various stages of of heavy-chain transcripts following the pre-B cell stage lead to syn- B-cell development:: some are indicated by the co-expression of IgD and IgM on the membrane. This The Pre-B-Cell Receptor Is Essential progression involves a change in RNA processing of the for B-Cell Development heavy-chain primary transcript to permit production of two mRNAS, one encoding the membrane form of the u chain As we saw in Chapter 10, during one stage in T-cell develop- and the other encoding the membrane form of the 8 chain ment, the p chain of the T-cell receptor associates with pre- (see Figure 5-19). Although IgD is a characteristic cell-surface Ta to form the pre-T-cell receptor(see Figure 10-1).A marker of mature naive B cells, its function is not clear How- parallel situation occurs during B-cell development. In the ever, since immunoglobulin 8 knockout mice have essentially pre-B cell, the membrane u chain is associated with the sur- normal numbers of fully functional B cells, IgD is not essen- rogate light chain, a complex consisting of two proteins: a tial to either B-cell development or antigen responsiveness. V-like sequence called Vpre- B and a C-like sequence calledby the co-expression of IgD and IgM on the membrane. This progression involves a change in RNA processing of the heavy-chain primary transcript to permit production of two mRNAs, one encoding the membrane form of the chain and the other encoding the membrane form of the  chain (see Figure 5-19). Although IgD is a characteristic cell-surface marker of mature naive B cells, its function is not clear. How￾ever, since immunoglobulin  knockout mice have essentially normal numbers of fully functional B cells, IgD is not essen￾tial to either B-cell development or antigen responsiveness. The Pre–B-Cell Receptor Is Essential for B-Cell Development As we saw in Chapter 10, during one stage in T-cell develop￾ment, the  chain of the T-cell receptor associates with pre￾T to form the pre–T-cell receptor (see Figure 10-1). A parallel situation occurs during B-cell development. In the pre-B cell, the membrane chain is associated with the sur￾rogate light chain, a complex consisting of two proteins: a V-like sequence called Vpre-B and a C-like sequence called 250 PART II Generation of B-Cell and T-Cell Responses FIGURE 11-3 Sequence of events and characteristics of the stages in B-cell maturation in the bone marrow. The pre-B cell expresses a membrane immunoglobulin consisting of a heavy (H) chain and sur￾rogate light chains, Vpre-B and 5. Changes in the RNA processing of heavy-chain transcripts following the pre-B cell stage lead to syn￾thesis of both membrane-bound IgM and IgD by mature B cells. RAG-1/2 = two enzymes encoded by recombination-activating genes; TdT = terminal deoxyribonucleotidyl transferase. A number of B-cell– associated transcription factors are important at various stages of B-cell development; some are indicated here. IgM IgD IgM VL J VHDH L JH PRO-B CELL PRE-B CELL MATURE B CELL IMMATURE B CELL H-chain genes L-chain genes DH JH VHDH JH DH JH RAG-1/2 TdT VL JL Surrogate Vpre-B and λ5 Germ-line κ and λ + + − − + − − − Heavy chain − µ µ + δ Membrane Ig Transcription factors Surface markers BSAP(Pax-5) Sox-4 EBF E2A Oct-2 c-Kit CD45R, CD19, HSA(CD24), Ig-α/Ig-β IL-7R CD43 Light chain Surrogate light chain Surrogate light chain LYMPHOID STEM CELL Germ line Germ line − − − Pu.1, Ikaros, others − κ or λ CD25 mIgM mIgD IgM Periphery antigen-dependent Bone marrow antigen-independent NAIVE B CELL − − Surrogate Vpre-B and λ5 Germ-line κ and λ Surrogate light chain of pre-BCR Ig-α/Ig-β