6. Lymphocyte development

Lymphocyte Development Overview

  • Lymphocytes arise from hematopoietic stem cells in the bone marrow.

  • Lymphopoiesis refers to the production of new lymphocytes, occurring in primary lymphoid tissues: bone marrow (B cells) and thymus (T cells).

  • New lymphocytes migrate to secondary lymphoid tissues (spleen, lymph nodes, mucosal lymphoid tissues) for immune responses.

B Cell Development

Differentiation from Hematopoietic Stem Cells

  • Hematopoietic Stem Cells (HSC):

    • Differentiate into multipotent progenitor cells (MPP) which can generate myeloid and lymphoid cells, but are not self-renewing.

    • Common lymphoid progenitor (CLP) cells emerge from MPP, responsible for B, T, and NK cells.

    • Three subsets of CLP:

      • Broad potential (B, T, NK cells)

      • B and T cell potential only

      • B cell committed subset releases B cells only.

Essential Factors for B Cell Development in Bone Marrow

  • IL-7: Critical for growth and survival of developing B cells.

  • Stem Cell Factor (SCF): Interacts with Kit receptor on B cells to stimulate growth.

  • Cell Adhesion Molecules & CXCL12: Required for retaining developing B cells in the bone marrow.

  • Thymic Stroma-Derived Lymphopoietin (TSLP): Functions similarly to IL-7.

  • Transcription Factors: E2A, early B cell factor (EBF), Pax5/BSAP are involved in regulation.

Gene Rearrangement in B Cell Development

  • E2A and EBF induce recombinase component expression to start heavy chain rearrangement in early pro-B cells.

  • Heavy chain pairs with surrogate light chains (λ5 and VpreB) for pre-B receptor formation.

  • Pre-B receptor signaling halts further heavy chain rearrangement and enhances IL-7 sensitivity for cell proliferation.

  • Light chain gene rearrangement starts in pre-B cells for functional B cell receptor maturation.

Immature B Cell Testing

  • Autoreactive immature B cells face:

    • Receptor Editing: New receptors are produced.

    • Apoptosis: Clonal deletion occurs.

    • Anergy: A permanent unresponsive state.

    • Immunological Ignorance: Can be activated under specific circumstances.

Maturation in the Spleen

  • Immature B cells differentiate into T1 and T2 transitional stages based on CD21 expression.

  • BAFF (B cell Activating Factor): Critical for survival signals from follicular dendritic cells.

  • Fully mature B cells express high IgD and low IgM and are primarily found as follicular B cells.

B-1 B Cells

  • B-1 B Cells: A subset of innate lymphocytes, produced primarily in the fetal liver with natural antibodies.

  • Spontaneously produce antibodies without T cell help, mainly responding to carbohydrates.

T Cell Development

Origin and Thymus Development

  • T cell progenitors migrate from the bone marrow to the thymus.

  • Signals from thymic epithelial cells via the Notch1 receptor guide commitment to T cell lineage.

  • Thymocytes undergo development stages: double negative (DN), double positive (DP) and single positive (SP) in the thymus.

  • Only 2-4% of thymocytes mature while the rest undergo apoptosis.

Stages of T Cell Maturation

DN Stage

  • DN is subdivided into DN1-4 based on CD44 and CD25.

  • TCR β-chain rearrangement occurs in DN2 thymocytes; pre-T cell receptor is formed in DN3.

Selection Process

  • Positive Selection: DP thymocytes bind self-peptide:self-MHC, essential for survival; 10-30% survive.

  • Negative Selection: Thymocytes with strong self-reactivity undergo apoptosis, occurring in both the cortex and medulla of the thymus.

Final Maturation

  • In the thymic medulla, mature T cells express specific receptors (S1PR1 for S1P) for exiting the thymus and CD62L for lymph node homing.

  • Autoreactive T cells may face elimination post-activation or become anergic.

γδ T Cell Development

  • Majority of γδ T cells arise during embryonic and early neonatal development.