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
- Primary: participates in the initial generation of B and T lymphocytes:
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
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: 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
Regulation
| Cytokines | Activities | Source |
|---|---|---|
| Stem cell factor (SCF) | Stimulates all hematopoietic progenitor cells | Bone marrow stromal cells |
| Interleukin-2 (IL-2) |
| T helper cells |
| Interleukin-4 (IL-4) |
| T helper cells |
| Interleukin-6 (IL-6) |
|
|
| Interleukin-7 (IL-7) | Stimulation of all lymphoid stem cells | Bone 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)
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 4.0Stages
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.
| Maturation stage | Ig genes | BCR | Associated events |
|---|---|---|---|
| Pre-pro-B cell | Germline DNA | None | No heavy or light chain expression |
| Pro-B cell | IGH D-J rearranged | None | Starts to express CD19, CD34, and HLA-DR (class II histocompatibility antigen) |
| Pre-B cell | IGH V-D-J rearranged | Pre-BCR is formed:
| Other markers appear (e.g., CD79, CD10, CD20, CD40, TdT) |
| Immature B cell |
| 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) |
| With mature BCR (IgM) → exit bone marrow | Expression of CD19 and CD20 by all |
BCR: B cell receptor
IGH: immunoglobulin heavy chain
Variable region (V)
Diversity segment (D)
Joining region (J)
TdT: terminal deoxytransferase
| Maturation stage | BCR | Associated 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 cell | Class-switch | Once activated, can remain as IgM or switch to IgE, IgG, or IgA |
| Memory B cell |
| |
| Plasma 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.
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)
Image: “Antigen receptor chem114A” by Tinastella. License: Public DomainStages
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.
| Maturation stage | T cell receptor | Associated events |
|---|---|---|
| Progenitor cells | None |
|
| Double-negative cells | Rearrangement of β chain (pre-TCR) (failure to rearrange leads to apoptosis) |
|
| Double-positive cells | Rearrangement of ɑ chain → ɑ chains assemble with β chains → complete ɑ-β–TCR-CD3 complex (expressed on the surface) |
|
| Single-positive T cells |
|
TCR: T cell receptor
Th: T helper cells
Tc: cytotoxic T cells
APCs: antigen-presenting cells
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.
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
- 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
- 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
- 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§ionid=137394642
- Mescher, A.L. (Ed.). (2021). Hemopoiesis. Junqueira’s Basic Histology Text and Atlas, 16e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=3047§ionid=255121548
- 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§ionid=252532359
- 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§ionid=252532458
