Development of T Lymphocytes Study Notes

Chapter 7: Development of T Lymphocytes

Overview of T Cell Development

  • Development process involves:

    • The development of T cells in the thymus.

    • Stages of gene rearrangement producing the primary repertoire of T-cell receptors.

    • Positive and negative selection of T-cell repertoire to yield a mature, naïve T cell population.

Comparison of T and B Cell Development

  • Similarities between T and B lymphocyte development:

    • Both derive from bone marrow stem cells.

    • Both undergo gene rearrangement for antigen receptors.

    • B cells rearrange in the bone marrow.

    • T cell precursors leave the bone marrow to migrate to the thymus.

    • Formation of two distinct T-cell lineages:

    • α:β Receptors (1-2% of the primary repertoire leaves the thymus),

    • γ:δ Receptors (less stringent selection).

Primary Lymphoid Tissue for T Cell Development

  • The thymus is a crucial organ for T cell maturation:

    • Ensures that mature T cells are restricted to recognizing a person's self-MHC (Major Histocompatibility Complex).

    • Two critical selection processes:

    • Positive Selection: Eliminates immature T cells with receptors that do not interact with any self-MHC class I or II.

    • Negative Selection: Eliminates immature T cells that are autoreactive (receptors binding too strongly to self-MHC).

    • Characteristics of mature T cells leaving the thymus:

    • Tolerant of self-antigens,

    • Responsive to foreign antigens,

    • Ready to combat infections.

Development Process of T Cells in the Thymus

  • Origin and migration:

    • T cells originate from bone marrow and mature in the thymus as thymus-dependent lymphocytes.

    • Majority develop into α:β T cells; minority are γ:δ T cells.

    • Development occurs in distinct parallel lineages from common precursors.

Expression of Surface Proteins in Thymocytes

  • While developing in the thymus, T cells express:

    • CD4 and CD8 glycoproteins, essential for their functions.

Thymus Anatomy and Function

  • Location:

    • Located in the upper anterior thorax above the heart.

  • Contains:

    • Immature T cells (thymocytes) embedded in an epithelial network (thymic stroma).

    • Functions in T cell development, not lymphocyte recirculation (only blood routes).

Structure During Embryonic Development

  • Epithelial cells of the cortex (outer) and medulla (inner).

  • The initial rudimentary thymus (thymic anlage) colonized by bone marrow-derived cells.

  • Thymocytes and dendritic cells populate the medulla, while macrophages are present throughout.

Cellular Organization of the Thymus

  • Thymic macrophages eliminate improperly matured thymocytes.

  • Characteristic features:

    • Hassall’s corpuscles located in the medulla are sites of cell destruction.

    • Differentiation between darker cortex and lighter medulla (observed in hematoxylin and eosin-stained sections).

Example of Developmental Disorder: DiGeorge’s Syndrome

  • Example where a deletion in chromosome 22 results in failure to develop a functional thymus, leading to absence of T cells and susceptibility to infections resembling SCID (severe combined immunodeficiency disease).

Aging and the Thymus

  • Thymus is most active in youth and progressively atrophies with age (thymic involution).

  • Despite reduced T cell production with aging, T cell immunity remains intact, and thymectomy does not affect adult immunity.

Lifespan of T Cells

  • Established repertoire of mature peripheral T cells are long-lived and self-renewing.

  • Unlike B cells, which are short-lived and continuously replenished by bone marrow.

T-cell Lineage Development

  • Maturation of thymocytes into T cells occurs through distinct stages marked by changes in:

    • TCR gene status,

    • TCR protein expression,

    • Production of surface glycoproteins (CD4, CD8, CD3 complex).

Progenitor T Cells

  • Initial progenitor T cells enter the thymus without surface glycoproteins but express CD34, characteristic of stem cells.

  • TCR genes are in germline configuration until interaction with thymic stromal cells leads to proliferation and differentiation.

  • Key molecules:

    • IL-7 receptor for binding IL-7 from stromal cells, guiding maturation.

    • Notch 1 signaling drives differentiation, maintaining the T-cell lineage.

TCR Rearrangement Process

  • Commitment to a specific lineage occurs through a competition to achieve productive TCR rearrangement.

  • Thymocytes rearrange β, γ, and δ chain genes simultaneously:

    • Successful rearrangement may lead to γ:δ or α:β T cells depending on timing of rearrangements.

  • Pre-T Cell Receptor:

    • Formed from successful β chain and surrogate α chain (Pre-Tα) assembly, signaling cessation of β chain rearrangement and initiation of proliferation.

Further Gene Rearrangements

  • After pre-TCR expression, the recombination machinery targets the α chain loci:

    • Majority of cells will successfully rearrange α chains first, leading to α:β T cells,

    • Cell death for cells where productive rearrangement fails occurs by apoptosis (98% of thymocytes).

Selection Processes: Positive and Negative Selection

  • Positive Selection involves selecting T cells that bind to self-MHC:

    • Takes place in the cortex, driven by epithelial cells presenting self-peptides.

    • Only 2% of thymocytes survive this selection process.

Mechanism of Positive Selection

  • Double-positive thymocytes interact with cortical epithelial cells presenting self-peptides via MHC:

    • Strong interactions promote survival, while weak/no interactions result in apoptosis.

  • Determines whether thymocytes express either CD4 or CD8, producing single-positive T cells.

Negative Selection

  • Removes T cells that bind too strongly to self-MHC/self-peptides:

    • Central tolerance; most crucial cells for this process include dendritic cells and macrophages.

    • self-peptides presented through AIRE-mediated processes ensure effective deletion of autoreactive T cells.

Role of Regulatory T Cells

  • CD4 T cells express patterns unique to regulatory T cells (e.g., CD25 and FoxP3).

  • Regulatory T cells suppress the response of naive T cells to self-antigens, requiring direct contact and the provision of non-inflammatory cytokines.

Conclusion

  • Upon selection, mature naïve T cells recirculate to secondary lymphoid organs.

  • Post-selection, T cells undergo differentiation into effector cells capable of responding to infections, with CD4 T cells maturing into distinct types based on the nature of the pathogen encountered, while CD8 T cells become cytotoxic, underscoring the complexity of adaptive immunity.