Lymphocyte Development

Abstract

Like haematopoietic cells of other lineages, both B and T lymphocytes arise from haematopoietic stem cells. Although B‐cell development takes place in the bone marrow, T cells are generated in the thymus. With the support of specialised micro‐environmental milieus, the progenitors unfold intrinsic genetic programs and progress through multiple intermediate stages to develop into antigen‐responsive lymphocytes. A constant theme during this process is lineage diversification. The role of several critical factors has been revealed in recent years, including that of transcription factor Pax5 (paired box 5) and Notch1 signal in B‐ and T‐lineage specification and commitment. In addition, lymphoid development is characterised by somatic recombination of the genes encoding antigen receptors. Such a process ensures the generation of an extremely diversified repertoire of antigen receptors. This newly generated repertoire is then subjected to strict selection before being added to the peripheral pool of mature lymphocytes.

Key Concepts:

  • The differentiation from haematopoietic stem cells to antigen‐responsive mature lymphocytes is accompanied by sequential changes in gene expression and orderly rearrangements of the genes encoding antigen receptors.

  • Division of the lymphoid developmental pathways into multiple stages provides a useful framework to dissect the cellular and molecular mechanisms of cell differentiation. But it should be recognised that the transition from one stage to the next is not necessarily as sharp as implied in the diagram.

  • Lineage specification and commitment is a protracted process, during which cells destined for one lineage does not lose potentials for alternative lineages until relatively late. It is always important to distinguish potential from predominant cell fate.

  • Cells at different developmental stages are associated with specialised micro‐environmental niches, and migration in and out of these niches is essential for the orderly progression of differentiation.

  • The micro‐environmental milieus either determine the fate to be adopted by a progenitor or provide signals to allow cell‐intrinsic developmental programs to progress.

  • Lymphocyte development is an expensive process for the host as the majority of the developing cells die by apoptosis as the result of selection against cells with nonproductively rearranged antigen receptor genes, cells incapable of recognising self‐MHC, or cells reactive to self‐antigens.

  • The quantitative differences in signal strength have a remarkable impact on fate choice by developing lymphocytes, such as positive‐versus‐negative selection, αβ‐versus‐γδ‐lineage diversification, CD4‐versus‐CD8‐lineage decision and Treg cell development.

Keywords: lymphocytes; differentiation; development; T cell; B cell; lineage commitment; gene rearrangement; negative selection; positive selection

Figure 1.

The developmental pathway of B lymphocytes. The common lymphoid progenitors (CLPs) represent the earliest precursors showing a clear bias towards the B lineage. Full commitment, however, is not achieved until the pro‐B stage. Several transcription factors, including E2A, EBF1 and Pax5, play crucial roles in the commitment. Pro‐B cells begin to rearrange the immunoglobulin (Ig) heavy chain locus. Productive rearrangement leads to the formation of the pre‐B‐cell receptor (pre‐BCR), which signals the progression to the pre‐B stage. On completion of light chain rearrangement, surface IgM containing both heavy and light chains first appears on immature B cells. Further maturation primarily occurs in the spleen, where cells progress through transitional stages (T1 and T2) to eventually develop into immunocompetent mature B cells marked by the co‐expression of surface IgM and IgD. The differentiation from immature to mature B cells is accompanied by negative selection against autoreactive B cells as BCR engagement by self‐antigens in immature and transitional B cells results in cell death rather than activation. An alternative mechanism of negative selection involves receptor editing to create a new BCR by bone marrow immature B cells.

Figure 2.

Germline configuration of the immunoglobulin (Ig) heavy chain and κ and λ light chain loci. The variable domain of the heavy chain is encoded by V, D and J segments, whereas that of the light chain is encoded by V and J segments. Each V segment is preceded by a small exon encoding a short leader (L) peptide. The numbers in parentheses indicate the approximate numbers of each segment found in germline DNA in the mouse. Pseudogenes are indicated with the Greek letter Ψ.

Figure 3.

Gene rearrangements during B‐cell development. The left panel shows the sequence of events occurring in the light (L)‐chain locus. In this illustration a V segment Vκ1 recombines with Jκ1 to generate the coding sequence for the variable domain. Subsequent ribonucleic acid (RNA) processing yields a full‐length messenger RNA (mRNA) encoding the whole of the L chain. The right panel shows a similar sequence of events in the heavy (H) chain locus: DJ joining occurs first, followed by V to DJ recombination, RNA processing and finally translation of the full‐length polypeptide. The four‐chain structure of the immunoglobulin (Ig) M molecule is shown at the bottom of the figure; this is associated with two invariant polypeptides Ig‐α and Ig‐β, which transduce signals into the cell following receptor crosslinking.

Figure 4.

The developmental pathway of T lymphocytes and the directional migration of developing T cells in the thymus. On the basis of CD4 and CD8 expression, T‐cell development is roughly divided into three main stages: the double‐negative (DN), the double‐positive (DP) and the single‐postive (SP). The DN cells are further resolved into four subsets (DN1–DN4) according to c‐kit, CD44 and CD25 expression. After seeding the thymus via the corticomedullary junction, the DN progenitors gradually acquire lineage specificity while moving outward in the cortex. T lineage‐committed cells (DN3) are found in the subcapsular zone, where they undergo pre‐TCR‐mediated β‐selection before proceeding to the DP stage. DP cells then migrate backward through the cortex. By interaction with MHC molecules on cortical thymic epithelial cells (cTECs), these cells undergo positive selection and CD4/CD8 lineage diversification. The CCR7‐mediated signal directs SP cells to the medulla, where negative selection occurs against cells bearing high‐affinity receptors for self‐peptides presented by medullary thymic epithelial cells (mTECs) or dendritic cells (DCs). Post‐selected SP cells are eventually exported to the periphery in response to S1P1‐mediated signals.

Figure 5.

Germline configuration of the TCR α, β, γ and δ chain loci. The variable domain of the β and δ chains is encoded by V, D and J segments, whereas that of the α and γ chains is encoded by V and J segments. Each V segment is preceded by a small exon encoding a short leader (L) peptide. The numbers in parentheses indicate the average numbers of each segment (including pseudogenes) for different mouse strains. Of note, the δ chain gene segments are embedded in the α chain locus, so that, rearrangement of the α chain leads to deletion of the whole δ locus.

Figure 6.

Affinity hypothesis of positive or negative selection of T cells. (a) A thymocyte whose T‐cell antigen receptor (TCR) recognises self‐peptide (green) in association with the major histocompatibility complex (MHC) (shown schematically as class II) on the surface of thymic antigen‐presenting cells (APCs) with negligible affinity. These cells die by apoptosis (called ‘death by neglect’). (b) A T cell that recognises the peptide–MHC complex with intermediate affinity. Signals generated via the TCR promote survival of such cells and their eventual recruitment into the periphery. (c) A T cell that recognises self‐peptide–MHC complex with high affinity. In this case signalling via the TCR induces these cells to undergo apoptosis.

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References

Buckley RH (2004) Molecular defects in human severe combined immunodeficiency. Annual Review of Immunology 22: 625–655.

Ciofani M and Zuniga‐Pflucker JC (2007) The thymus as an inductive site for T lymphoiesis. Annual Review of Cell and Developmental Biology 23: 463–493.

Dias S, Xu W, McGregor S and Kee B (2008) Transcriptional regulation of lymphocyte development. Current Opinion in Genetics and Development 18: 441–448.

Hardy RR, Kincade PW and Dorshkind K (2007) The protean nature of cells in the B lymphocyte lineage. Immunity 26: 703–714.

Hayakawa K and Hardy RR (2000) Development and function of B‐1 cells. Current Opinion in Immunology 12: 346–353.

Monroe JG and Dorshkind K (2007) Fate decisions regulating bone marrow and peripheral B lymphocyte development. Advances in Immunology 95: 1–50.

Peterson P, Org T and Rebane A (2008) Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nature Reviews. Immunology 8: 948–957.

Petrie HT and Zuniga‐Pflucker JC (2007) Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annual Review of Immunology 25: 649–679.

Sakaguchi S, Yamaguchi T, Nomura T and Masahiro O (2008) Regulatory T cells and immune tolerance. Cell 133: 775–787.

Sebzda E, Mariathasan S, Ohteki T et al. (1999) Selection of the T cell repertoire. Annual Review of Immunology 17: 829–874.

Spicuglia S, Franchini DM and Ferrier P (2006) Regulation of V(D)J recombination. Current Opinion in Immunology 18: 158–163.

Taghon T and Rothenberg EV (2008) Molecular mechanisms that control mouse and human TCR‐ab and TCR‐gd T cell development. Seminars in Immunopathology 30: 383–398.

Further Reading

Abbas AK, Lichtman AH and Pillai S (2007) Cellular and Molecular Immunology, 6th edn. Philadelphia, PA: Saunders.

Kindt TJ, Goldsby RA and Osborne BA (2007) Immunology, 6th edn. New York: W.H. Freeman & Company.

Male D, Brostoff J, Roth D and Roitt I (2006) Immunology, 7th edn. London: Mosby.

Murphy KM, Travers P and Walport M (2007) Immunobiology: The Immune System, 7th edn. New Yowk: Garland Science.

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Zhang, Yu(Apr 2010) Lymphocyte Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001192.pub2]