Lymphoid Development

Abstract

Lymphocytes, which are white blood cells, comprise a fundamentally important compartment of the immune system since they are key players in controlling how specific and effective an immune response is to infectious microbes or foreign agents. Lymphocytes exist as three distinct cell lineages, namely Bursa‐derived lymphocytes (B cells), thymus‐derived lymphocytes (T cells) and innate lymphoid cells (ILCs). While B cells and T cells mediate antigen‐specific or adaptive immunity, ILCs mediate preformed or innate immunity. This review discusses the development of B cells, T cells and specifically NK cells, a type of ILC. It details the localisation of development, the selection process these cells face and modifications they may undergo throughout their maturation and localisation to other tissues. The modifications described include functional changes as well as changes in the expression of intracellular and surface molecular markers.

Key Concepts:

  • As proponents of the adaptive immune response, each B cell and T cell express a single unique antigen‐specific receptor providing the host with a large spectrum of specificities, also known as a repertoire.

  • B and T cells must be eliminated during their selection process or selected to develop further into a more specialized immune regulatory cell to avoid autoreactivity.

  • B cell lymphopoiesis is largely confined to the bone marrow and is defined cell size, immunoglobulin gene rearrangement status, activity of transcription factors and expression of cell surface molecules.

  • Peripheral tolerance mechanisms ensure that B cells which survived central tolerance mechanisms become anergic or unresponsive upon encounter of self‐antigen in the periphery.

  • T cell development in the thymus is highly regulated as the developing T cell progenitor moves through the specialized thymic niches and interacts with resident thymic stromal cells, including cortical thymic epithelial cells (cTECs), medullary TECs (mTECs), fibroblasts, dendritic cells and other haematopoietically derived stroma cells.

  • During development in the thymus, T cells undergo both positive and negative selection to eliminate potentially self‐reactive cells.

  • The thymus also promotes the selection of naturally occurring regulatory T cells, namely NK T cells, CD8aa+ intraepithelial (nIEL) T cells, regulatory T (nTreg) cells and IL‐17 producing T (nTh17) cells, which can actively suppress self‐reactive T cells.

  • NK cells are important for host defence against malignantly transformed and virally infected cells and against some bacterial and parasitic infections.

  • NK cells are regulated by signalling downstream of activating and inhibitory germline encoded receptors.

  • NK cells undergo an education process to insure self‐tolerance.

Keywords: lymphocytes; B cells; T cells; innate lymphoid cells; natural killer (NK) cells; common lymphoid progenitor; receptor rearrangement; thymocyte selection; regulatory T cells; NK cell licensing

Figure 1.

Schematic depiction of B cell development. See text for details.

Figure 2.

Schematic depiction of T cell development in the thymus. See text for details.

Figure 3.

Schematic depiction of transcription factors and key surface markers in NK cell development. Peripheral blood NK cells develop from a bone marrow HSC via a CLP intermediate. Surface markers and transcription factors expressed by NK cells at different stages of maturity are indicated.

close

References

Akiyama T, Shinzawa M, Qin J and Akiyama N (2013) Regulations of gene expression in medullary thymic epithelial cells required for preventing the onset of autoimmune diseases. Frontiers in Immunology 4: 249.

Anderson G and Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends in Immunology 33: 256–263.

Baumgarth N (2013) Innate‐like B cells and their rules of engagement. Advances in Experimental Medicine and Biology 785: 57–66.

Benson MJ, Erickson LD, Gleeson MW and Noelle RJ (2007) Affinity of antigen encounter and other early B‐cell signals determine B‐cell fate. Current Opinion in Immunology 19: 275–280.

Boehm T (2012) Self‐renewal of thymocytes in the absence of competitive precursor replenishment. Journal of Experimental Medicine 209: 1397–1400.

Born WK, Yin Z, Hahn YS, Sun D and O'Brien RL (2010) Analysis of gamma delta T cell functions in the mouse. Journal of Immunology 184: 4055–4061.

Cambier JC and Getahun A (2010) B cell activation versus anergy; the antigen receptor as a molecular switch. Immunology Letters 128: 6–7.

Ciofani M and Zuniga‐Pflucker JC (2005) Notch promotes survival of pre‐T cells at the beta‐selection checkpoint by regulating cellular metabolism. Nature Immunology 6: 881–888.

Cooper MA, Fehniger TA and Caligiuri MA (2001) The biology of human natural killer‐cell subsets. Trends in Immunology 22: 633–640.

Di Santo JP (2006) Natural killer cell developmental pathways: a question of balance. Annual Review of Immunology 24: 257–286.

Dorshkind K and Montecino‐Rodriguez E (2007) Fetal B‐cell lymphopoiesis and the emergence of B‐1‐cell potential. Nature Reviews Immunology 7: 213–219.

Eason DD, Cannon JP, Haire RN et al. (2004) Mechanisms of antigen receptor evolution. Seminars in Immunology 16: 215–226.

Fathman JW, Bhattacharya D, Inlay MA et al. (2011) Identification of the earliest natural killer cell‐committed progenitor in murine bone marrow. Blood 118: 5439–5447.

Fontenot JD, Gavin MA and Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunology 4: 330–336.

Freud AG and Caligiuri MA (2006) Human natural killer cell development. Immunological Reviews 214: 56–72.

Gaffen SL (2011) Recent advances in the IL‐17 cytokine family. Current Opinion in Immunology 23: 613–619.

Girardi E and Zajonc DM (2012) Molecular basis of lipid antigen presentation by CD1d and recognition by natural killer T cells. Immunological Reviews 250: 167–179.

Goldschneider I (2006) Cyclical mobilization and gated importation of thymocyte progenitors in the adult mouse: evidence for a thymus‐bone marrow feedback loop. Immunological Reviews 209: 58–75.

Gordon J and Manley NR (2011) Mechanisms of thymus organogenesis and morphogenesis. Development 138: 3865–3878.

Griesemer AD, Sorenson EC and Hardy MA (2010) The role of the thymus in tolerance. Transplantation 90: 465–474.

Hardy RR (2006) B‐1 B cells: development, selection, natural autoantibody and leukemia. Current Opinion in Immunology 18: 547–555.

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

Held W, Dorfman JR, Wu MF and Raulet DH (1996) Major histocompatibility complex class I‐dependent skewing of the natural killer cell Ly49 receptor repertoire. European Journal of Immunology 26: 2286–2292.

Hoglund P and Brodin P (2010) Current perspectives of natural killer cell education by MHC class I molecules. Nature Reviews Immunology 10: 724–734.

Inlay MA, Bhattacharya D, Sahoo D et al. (2009) Ly6d marks the earliest stage of B‐cell specification and identifies the branchpoint between B‐cell and T‐cell development. Genes & Development 23: 2376–2381.

Jenne CN, Enders A, Rivera R et al. (2009) T‐bet‐dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. Journal of Experimental Medicine 206: 2469–2481.

Kim S, Poursine‐Laurent J, Truscott SM et al. (2005) Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436: 709–713.

Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nature Immunology 9: 495–502.

Luevano M, Madrigal A and Saudemont A (2012) Transcription factors involved in the regulation of natural killer cell development and function: an update. Frontiers in Immunology 3: 319.

Mansour A, Anginot A, Mancini SJ et al. (2011) Osteoclast activity modulates B‐cell development in the bone marrow. Cell Research 21: 1102–1115.

Melchers F, ten Boekel E, Seidl T et al. (2000) Repertoire selection by pre‐B‐cell receptors and B‐cell receptors, and genetic control of B‐cell development from immature to mature B cells. Immunological Reviews 175: 33–46.

Meng W, Yunk L, Wang LS et al. (2011) Selection of individual VH genes occurs at the pro‐B to pre‐B cell transition. Journal of Immunology 187: 1835–1844.

Montecino‐Rodriguez E and Dorshkind K (2012) B‐1 B cell development in the fetus and adult. Immunity 36: 13–21.

Moran AE and Hogquist KA (2012) T‐cell receptor affinity in thymic development. Immunology 135: 261–267.

Narni‐Mancinelli E, Chaix J, Fenis A et al. (2011) Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor. Proceedings of the National Academy of Sciences of the USA 108: 18324–18329.

O'Leary JG, Goodarzi M, Drayton DL and von Andrian UH (2006) T cell‐ and B cell‐independent adaptive immunity mediated by natural killer cells. Nature Immunology 7: 507–516.

Ohkura N, Kitagawa Y and Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38: 414–423.

Peng H, Jiang X, Chen Y et al. (2013) Liver‐resident NK cells confer adaptive immunity in skin‐contact inflammation. Journal of Clinical Investigation 123: 1444–1456.

Pillai S and Cariappa A (2009) The follicular versus marginal zone B lymphocyte cell fate decision. Nature Reviews Immunology 9: 767–777.

Ramirez J, Lukin K and Hagman J (2010) From hematopoietic progenitors to B cells: mechanisms of lineage restriction and commitment. Current Opinion in Immunology 22: 177–184.

Rothenberg EV, Moore JE and Yui MA (2008) Launching the T‐cell‐lineage developmental programme. Nature Reviews Immunology 8: 9–21.

Spits H and Cupedo T (2012) Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annual Review of Immunology 30: 647–675.

Starr TK, Jameson SC and Hogquist KA (2003) Positive and negative selection of T cells. Annual Review of Immunology 21: 139–176.

Takahama Y (2006) Journey through the thymus: stromal guides for T‐cell development and selection. Nature Reviews Immunology 6: 127–135.

Tripathy SK, Keyel PA, Yang L et al. (2008) Continuous engagement of a self‐specific activation receptor induces NK cell tolerance. Journal of Experimental Medicine 205: 1829–1841.

Warr MR, Pietras EM and Passegue E (2011) Mechanisms controlling hematopoietic stem cell functions during normal hematopoiesis and hematological malignancies. Wiley Interdisciplinary Reviews Systems Biology and Medicine 3: 681–701.

Welinder E, Ahsberg J and Sigvardsson M (2011) B‐lymphocyte commitment: identifying the point of no return. Seminars in Immunology 23: 335–340.

Wong GW and Zuniga‐Pflucker JC (2010) Gammadelta and alphabeta T cell lineage choice: resolution by a stronger sense of being. Seminars in Immunology 22: 228–236.

Xing Y, Li W, Lin Y et al. (2009) The influence of BCR density on the differentiation of natural poly‐reactive B cells begins at an early stage of B cell development. Molecular Immunology 46: 1120–1128.

Zuniga LA, Jain R, Haines C and Cua DJ (2013) Th17 cell development: from the cradle to the grave. Immunological Reviews 252: 78–88.

Further Reading

Bezman NA, Kim CC, Sun JC et al. (2012) Molecular definition of the identity and activation of natural killer cells. Nature Immunology 13: 1000–1009.

Carpenter AC and Bosselut R (2010) Decision checkpoints in the thymus. Nature Immunology 11: 666–673.

Elliott JM and Yokoyama WM (2011) Unifying concepts of MHC‐dependent natural killer cell education. Trends in Immunology 32(8): 364–372.

Gao Y, Lin F, Su J et al. (2012) Molecular mechanisms underlying the regulation and functional plasticity of FOXP3(+) regulatory T cells. Genes and Immunity 13: 1–13.

Hagman J, Ramirez J and Lukin K (2012) B lymphocyte lineage specification, commitment and epigenetic control of transcription by early B cell factor 1. Current Topics in Microbiology and Immunology 356: 17–38.

Hesslein DG and Lanier LL (2011) Transcriptional control of natural killer cell development and function. Advances in Immunology 109: 45–85.

Nagasawa T (2006) Microenvironmental niches in the bone marrow required for B‐cell development. Nature Reviews Immunology 6: 107–116.

Rowland SL, Tuttle K, Torres RM and Pelanda R (2013) Antigen and cytokine receptor signals guide the development of the naïve mature B cell repertoire. Immunologic Research 55: 231–240.

Spits H and Di Santo JP (2011) The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodelling. Nature Reviews Immunology 12: 21–27.

Stritesky GL, Jameson SC and Hogquist KA (2012) Selection of self‐reactive T cells in the thymus. Annual Review of Immunology 30: 95–114.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Collazo, Michelle M, Gumbleton, Matthew, and Kerr, William G(Jul 2014) Lymphoid Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000902.pub3]