Lymphocytes

Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. B and T lymphocytes play a role in adaptive immunity, and NK cells provide host defense against atypical proteins such as tumor cells. While all developmental stages begin in bone marrow, lymphocyte maturation differs. B lymphocytes and NK cells differentiate in bone marrow before migrating to secondary lymphoid organs (such as lymph nodes). T lymphocytes, however, proceed to the thymus for further maturation.

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Overview

Definitions and description

Lymphocytes are blood cells involved in immune response, which arise from the common lymphoid progenitor (CLP).

  • Description:
    • 30% of circulating WBCs
    • Spherical and/or ovoid cells
    • Diameter: 6–15 μm 
    • Lifespan: weeks to years
  • Belong to a heterogeneous group of cells called leukocytes (WBCs), which are divided as follows:
    • Granulocytes: derived from the myeloid progenitor
    • Agranulocytes: includes lymphocytes (from the lymphoid progenitor) and monocytes (from the myeloid progenitor) 
  • Type of lymphocytes and function:
    • B lymphocytes, or B cells (bursa derived): humoral adaptive immunity
    • T lymphocytes, or T cells (thymic derived): cell-mediated adaptive immunity
    • Natural killer (NK) cells: innate immunity with some adaptive immune response:
      • An important role in the host defense of tumor cells, virus-infected cells, and other atypical, “nonself” proteins
      • 5%–20% of lymphocytes in the peripheral blood
  • Lymphoid tissues involved:
    • Primary: participates in the initial generation of B and T lymphocytes:
      • Bone marrow
      • Thymus
    • Secondary: 
      • Lymph nodes
      • Spleen
      • Tonsils
      • Aggregations of lymphoid tissue in the GI and respiratory tracts

Structure

  • Difficult to distinguish types of lymphocytes on microscopy
  • Nucleus: 
    • Ovoid or kidney shaped with densely packed nuclear chromatin
    • Occupies approximately 90% of the cell (high nuclear-to-cytoplasmic ratio)
  • In the pale-blue cytoplasm:
    • Free ribosomes
    • Lysosomes
    • Rough-surfaced endoplasmic reticulum
    • Golgi
    • Mitochondria and centrioles are adjacent to the membrane.
  • Cytoskeletal proteins include tubulin, myosin, and actin (among others) arranged into microtubules and microfilaments.
  • Cytotoxic T lymphocytes and NK cells have abundant cytoplasmic granules:
    • Perforin: pore-forming proteolytic enzyme
    • Granzymes: serine proteinases facilitating apoptosis (stored as inactive proenzymes)
    • Serpins (serine-proteinase inhibitors): prevent autolysis by granules
White blood cells

White blood cells (WBCs), or leukocytes, in the blood:
Granulocytes include basophil, eosinophil, and neutrophil; agranulocytes include lymphocytes and monocytes.

Image: “Blausen 0909 WhiteBloodCells” by Blausen. License: CC BY 3.0

Lymphopoiesis

Lymphocyte production

  • Hematopoiesis:
    • 1st to 2nd month in utero: mesoderm of the yolk sac
    • By the 2nd month: moves to the liver (and spleen)
    • By the 5th month: occurs in the bone marrow, becoming the predominant source of blood cells
  • Lymphopoiesis starts with multipotent hematopoietic stem cells (HSCs) in the bone marrow.
  • HSCs → multipotent progenitor (MPP) cells → CLPs (becomes T cells, B cells, and NK cells):
    • B lymphocytes → peripheral lymphoid organs
    • Lymphocytes migrate to the thymus → T lymphocytes → peripheral lymphoid organs:
      • The thymus maintains the production of T cells until puberty.
      • By puberty, the thymus undergoes involution → ↓ lymphoid tissue mass and ↓ output of T cells
    • NK cells → peripheral lymphoid organs
Bone marrow hematopoiesis

Bone-marrow hematopoiesis: proliferation and differentiation of the formed elements of blood.
IL-3: interleukin-3
CFU-GEMM: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte
IL-2: interleukin-2
IL-6: interleukin-6
CFU-GM: colony-forming unit–granulocyte-macrophage
GM-CSF: granulocyte-macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
IL-5: interleukin-5
NK: natural killer
TPO: thrombopoietin
EPO: erythropoietin

Image by Lecturio. License: CC BY-NC-SA 4.0

Regulation

Table: Interleukins
CytokinesActivitiesSource
Stem cell factor (SCF)Stimulates all hematopoietic progenitor cellsBone marrow stromal cells
Interleukin-2 (IL-2)
  • Mitogen for activated T and B cells
  • Differentiation of NK cells
T helper cells
Interleukin-4 (IL-4)
  • Development of basophils and mast cells
  • Activation of B lymphocyte
T helper cells
Interleukin-6 (IL-6)
  • Mitogen for leukocytes
  • Activation of B cells and regulatory T cells
  • Macrophages
  • Neutrophils
  • Endothelial cells
Interleukin-7 (IL-7)Stimulation of all lymphoid stem cellsBone marrow stromal cells

B cells

Development

  • Starts in the bone marrow: HSCs → CLPs
  • In order to produce a functional, mature B cell from CLP:
    • Expression of the cell-surface Ig molecule (part of the B cell receptor (BCR))
    • Germline DNA does not have the complete genes to encode a complete Ig molecule.
    • Gene rearrangements (uniting different gene segments) within B cells are needed to assemble the Ig molecule.
    • The process also produces a repertoire of diverse B cells, creating protection against different kinds of infections.
  • Cell-surface (Ig) molecule:
    • Has heavy chains (μ, δ, γ, α, or ε) disulfide-linked to light chains (κ or λ)
    • Heavy chain genes (found within a single gene locus, IGH), are assembled from 4 gene segments:
      • Variable region (V)
      • Diversity segment (D)
      • Joining region (J)
      • Constant region (C)
    • The light chain genes (found as two separate gene loci-the κ locus [IGK] and the λ locus [IGL]) come from 3 gene segments:
      • Variable region (V)
      • Joining region (J) 
      • Constant region (C)
B-cell receptor (BCR)

The B cell receptor (BCR) consists of the immunoglobulin (Ig) molecule and the signaling molecule. Immunoglobin contains 2 identical heavy chains and 2 identical light chains linked by a disulfide bridge; the membrane-bound Ig is anchored to the cell surface.

Image: “Figure 42 02 06” by OpenStax. License: CC BY 4.0

Stages

To reach functionality, the B cell goes through stages in the bone marrow and the secondary lymphoid organs. 

  • In the initial stages occurring in the bone marrow, the aim is to build the receptor (requiring no antigen). 
  • When released to the secondary lymphoid organs, an antigen (with or without T cell help) will activate the B cell to continue the maturation process.
Table: Antigen-independent stages in B cell differentiation
Maturation stageIg genesBCRAssociated events
Pre-pro-B cellGermline DNANoneNo heavy or light chain expression
Pro-B cellIGH D-J rearrangedNoneStarts to express CD19, CD34, and HLA-DR (class II histocompatibility antigen)
Pre-B cellIGH V-D-J rearrangedPre-BCR is formed:
  • Heavy chain is present.
  • Surrogate light chain is present.
Other markers appear (e.g., CD79, CD10, CD20, CD40, TdT)
Immature B cell
  • IGH V-D-J rearranged
  • Light chain V-J rearranged
Mature BCR (IgM molecule)HLA-DR, CD19, CD20, and CD40 expression continues, but not other markers (e.g., CD10, CD34, TdT)
Mature B cell (naive)
  • IGH V-D-J rearranged
  • Light chain V-J rearranged
With mature BCR (IgM) → exit bone marrowExpression of CD19 and CD20 by all
Ig: immunoglobulin
BCR: B cell receptor
IGH: immunoglobulin heavy chain
Variable region (V)
Diversity segment (D)
Joining region (J)
TdT: terminal deoxytransferase
Table: Antigen-dependent stages in B-cell differentiation
Maturation stageBCRAssociated events
Mature B cell (in secondary lymphoid tissues)Mature (expresses IgM and IgD when in the secondary lymphoid tissues)Cells can rest, or B cell activation can occur (B cells interact with exogenous antigen and/or T helper cells).
Activated B cellClass-switchOnce activated, can remain as IgM or switch to IgE, IgG, or IgA
Memory B cell
  • Activated B cell → some become memory B cells
  • Circulate, react to antigen stimulation, generate plasma cells
Plasma cell
  • Activated B cell → some become plasma cells
  • Large cells secrete antibodies and fight infection
  • Migrate to the bone marrow
BCR: B cell receptor
Differentiation stages of the B cell

Differentiation stages of the B cell:
In antigen-independent stages, B cell production starts with the hematopoietic stem cell (HSC), which becomes a common lymphoid progenitor (CLP), then a pre-pro–B cell or B-progenitor cell. The next steps include gene rearrangement to assemble the immunoglobulin (Ig) molecule. Immunoglobulin heavy chains start with rearrangement of diversity and joining segments to form the pro-B cell. In the next step (pre-B cell), Ig heavy-chain recombination (variable, diversity, joining) is completed and the pre-B–cell receptor is formed. Light-chain (kappa (κ) or lambda (λ)) rearrangement occurs resulting in the expression of a complete IgM-antibody molecule by an immature B cell. Formation of the mature B cell (naive) with both IgM and IgD follows.
Antigen-dependent stages take place in secondary lymphoid tissues. Once the mature B cell produces IgM and IgD, a class-switch can take place to make IgE, IgG, and IgA. B cells are activated and become plasma cells or memory cells.

Image by Lecturio. License: CC BY-NC-SA 4.0

T cells

Development

  • HSCs → CLPs → early thymic progenitor cells → thymus
  • The developing T cells in the thymus are called thymocytes.
  • Gene rearrangements form the T cell receptor (TCR):
    • The majority of T cells contain ɑ and β chains and the coreceptors CD4 or CD8.
    • Remaining T cells contain ɣ and δ chains.
    • TCR + CD3 form the TCR complex.
    • CD3: The marker most commonly used to identify T cells.
Comparison of the B-cell receptor (BCR) and the T-cell receptor (TCR)

Comparison of the B cell receptor (BCR) and the T cell receptor (TCR)

Image: “Antigen receptor chem114A” by Tinastella. License: Public Domain

Stages

To reach functionality, the T cell goes through stages, released from the bone marrow as progenitor cells to continue development in the thymus. 

  • In the initial stages, the aim is to build the receptor (requiring no antigen). 
  • Further steps follow to activate the T cell (with an antigen) and to differentiate into either T helper cell or cytotoxic T cell.
Table: Stages of T-cell differentiation
Maturation stageT cell receptorAssociated events
Progenitor cellsNone
  • Bone marrow → thymus for further maturation
  • Become double-negative cells (still lacking CD4 and CD8)
Double-negative cellsRearrangement of β chain (pre-TCR) (failure to rearrange leads to apoptosis)
  • Expression of CD3
  • CD4-, CD8- (no CD4 and CD8)
Double-positive cellsRearrangement of ɑ chain → ɑ chains assemble with β chains → complete ɑ-β–TCR-CD3 complex (expressed on the surface)
  • CD4+, CD8+
  • Double-positive cells interact with self-antigens (in the context of MHC molecules)
  • With MHC presentation, some cells undergo positive selection in the thymic cortex:
    • Intermediate or moderate interaction between MHC and TCR
    • Production of functional cells
  • Some cells undergo negative selection in the thymic medulla:
    • High affinity or strong interaction between MHC and TCR
    • Cell death (apoptosis)
    • Prevents release of dysfunctional T cells (can activate autoimmunity)
  • Failure to interact → apoptosis
Single-positive T cells
  • Cell signals trigger the cellular expression of either CD4 or CD8 (not both).
    • Th with CD4: interact with cells to express MHC class II
    • Tc with CD8: interact with cells to express MHC class I
  • Naive Th and Tc circulate (blood → lymphoid tissues → lymph) and await activation by APCs (carrying a complementary peptide-MHC complex)
MHC: major histocompatibility complex
TCR: T cell receptor
Th: T helper cells
Tc: cytotoxic T cells
APCs: antigen-presenting cells
T Cell differentiation stages

Differentiation stages of T cell:
From the bone marrow, progenitor cells go to the thymus for further maturation. The double-negative cells (no expression of CD4/CD8 or CD4-/CD8 -) have not developed the T-cell receptor (TCR). The double-negative cells undergo rearrangement of the TCR gene and become pro-T cells, then pre-T cells. Through the series, CD4 and CD8 are expressed, and the TCR becomes assembled through gene rearrangements (double-positive cells). The thymus then presents major histocompatibility complex (MHC) molecules to the developing T cells. Some cells undergo positive selection (intermediate interaction between MHC and TCR takes place) and produce functional cells. Some cells undergo negative selection (strong interaction between MHC and TCR), which results in cell death. The release of dysfunctional T cells, which can activate autoimmunity, is prevented. Some T cells fail to interact, leading to apoptosis. Mature T cells express either CD4 (T helper cells) or CD8 (cytotoxic T cells), not both.

Image by Lecturio. License: CC BY-NC-SA 4.0

Natural Killer Cells

  • HSCs in the bone marrow → CLPs → lymphoblasts → prolymphocytes → NK cells
  • Production stimulated by interleukin-15 (IL-15)
  • Activated by exposure to virus-infected cells or cells with abnormal patterns of surface-antigen expression (cancer cells)
  • Also involved in antibody-dependent cell-mediated cytotoxicity (ADCC)

Clinical Relevance

  • Hodgkin lymphoma: malignancy of B lymphocytes originating in lymph nodes. The pathognomic finding is a Hodgkin/Reed-Sternberg (HRS) cell (a giant, multinucleated B cell with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, and fever. Splenomegaly or hepatomegaly may be present. Diagnostic testing includes lymph-node histological analysis to show HRS cells, blood tests, and imaging studies. 
  • Non-Hodgkin lymphoma (NHL): a diverse group of malignancies originating from B cells, T cells, or (rarely) NK cells. Two-thirds of NHLs involve lymph nodes; the remainder is extranodal. Non-Hodgkin lymphoma affects all ages. B-cell NHLs include Burkitt lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and marginal zone lymphoma. T-cell NHLs include adult T-cell lymphoma and mycosis fungoides. Common signs and symptoms are fever, weight loss, night sweats, lymphadenopathy, and hepatosplenomegaly.
  • Acute lymphoblastic leukemia: the most common form of cancer affecting children. Acute lymphoblastic leukemia is characterized by the uncontrolled proliferation of lymphoid precursor cells (increased lymphoblasts). Normal marrow is replaced by lymphoblasts, which go into circulation and infiltrate other organs. Signs and symptoms are related to anemia, thrombocytopenia, and lack of functional WBCs. Peripheral blood smear and bone marrow biopsy identify lymphoblasts. Immunophenotyping, histochemistry, and genetic studies aid in diagnosis and treatment.
  • Chronic lymphocytic leukemia: slow-growing blood and bone marrow cancer characterized by excess production of monoclonal-B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma. The disease usually presents asymptomatically in older adults. Diagnosis is made from abnormal lymphocytosis on laboratory testing. The B cells are functionally incompetent lymphocytes, which may result in recurrent infections. 
  • Multiple myeloma: a malignant condition of plasma cells (activated B lymphocytes). The monoclonal proliferation of plasma cells results in excessive secretion of IgG antibodies and cytokine-driven osteoclastic activity (bone pains, pathologic fractures, and metabolic disturbances). Excessive secretion of antibodies results in proteinuria, kidney damage, and production/tissue deposition of amyloid fibrils. Diagnosis is by plasma electrophoresis and bone marrow biopsy. 

References

  1. Abel, A., Yang, C., Thakar, M., Malarkannan, S. (2018). Natural Killer Cells: development, maturation and clinical utilization. Front. Immunol. 9, 1869. https://doi.org/10.3389/fimmu.2018.01869
  2. Aster, J. (2021). Normal B and T lymphocyte development. UpToDate. Retrieved June 24, 2021, from https://www.uptodate.com/contents/normal-b-and-t-lymphocyte-development
  3. Aster, J.C., & Scadden, D. (2016). Hematopoiesis. In Aster, J.C., & Bunn, H. (Eds.), Pathophysiology of Blood Disorders, 2e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=1900&sectionid=137394642
  4. Mescher, A.L. (Ed.). (2021). Hemopoiesis. Junqueira’s Basic Histology Text and Atlas, 16e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=3047&sectionid=255121548
  5. Muthusamy, N., & Caligiuri, M.A. (2021). The structure of lymphocytes and plasma cells. In Kaushansky K, et al.(Eds.), Williams Hematology, 10e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2962&sectionid=252532359
  6. Seet, C.S., & Crooks, G.M. (2021). Lymphopoiesis. In Kaushansky K, et al. (Eds.), Williams Hematology, 10e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2962&sectionid=252532458

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