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Chapter 2 Innate and Adaptive Immunity: From Cell Defense to Tissue Repair

Section 7:  T and B Lymphocyte Development and Selection

Zoë Soon

T Cell Development and Selection

T cells, arise from bone marrow hematopoietic cells and migrate to the thymus to mature through three stages.

1.  TCR Production:  In the thymic cortex, T cells undergo somatic recombination to express a unique and functional T Cell Receptor (TCR) and are then nurtured; those without a functional TCR undergo apoptosis (‘death by neglect’).

2.  Positive Selection:  In the next step of maturation, termed positive selection, the T cells encounter cortical thymocytes that display Major Histocompatibility Complex (MHC) molecules (self identity transmembrane protein complexes).  T cells that bind weakly or moderately to these MHC are chosen for further maturation, while those that do not bind or bind too strongly are eliminated.  At this point in time, the surviving T cells commit to expressing either CD8 or CD4 receptors before entering the thymic medulla, where negative selection occurs.

3.  Negative Selection:  T cells are exposed to medullary thymic cells and APCs that are displaying a large array of self-peptides on their MHC molecules.  T cells that bind too strongly are induced to undergo apoptosis to prevent autoimmunity.

Positive and Negative Selection:  Preventing Autoimmunity 

During Positive Selection in the Thymic Cortex:

CD4+ T cells Those that bind to thymic self-peptides displayed on MHC Class II molecules (MHC-II) are nurtured and develop CD4+ receptors → Positive Selection.

Those that either do not bind or bind too strongly to thymic self-peptide-MHC-II complexes undergo apoptosis (‘death by neglect’, preventing autoimmunity).
CD8+ T cells Those that bind to thymic self-peptides displayed on MHC Class I (MHC-I) are nurtured and develop CD8+ receptors → Positive Selection.

Those that either do not bind or bind too strongly to self MHC-I undergo apoptosis (‘death by neglect’, preventing autoimmunity).

During Negative Selection in the Thymic Medulla:

CD4+ T cells Those that weakly bind self-peptides displayed on MHC-II of APCs mature into CD4+ Effectors (Helper T cells).

Those binding moderately become CD4+ Regulatory T (Treg) cells that suppress effector T cell proliferation.

Those that strongly bind self-peptides displayed on MHC-II of APCs undergo apoptosis (‘death by neglect’, preventing autoimmunity).
CD8+ T cells Those that weakly bind self-antigens displayed on MHC-I of APCs mature into CD8+ Effectors (Cytotoxic T cells).

Those binding moderately become CD8+ Regulatory T cells.

Those that strongly bind self-antigens displayed on MHC-I of APCs undergo apoptosis (‘death by neglect’, preventing autoimmunity).

*Note: MHC (Major Histocompatibility Complex) proteins were previously known as HLA (Human Leukocyte Antigens).

MHC Class I are found on almost all nucleated cells in your body, and present normal antigens from self-proteins and will also present abnormal/foreign antigens when the cell is compromised.

MHC Class II are expressed only by APCs which include macrophages, dendritic cells, and B cells and are used to present phagocytosed foreign antigens to activate immune cells.

After negative selection, the T cells are now self-restricted and self-tolerant naïve T cells that can safely leave the thymus and enter the bloodstream and continuously recirculate through secondary lymphoid organs (like the spleen, lymph nodes, and tonsils) to patrol for foreign antigens.  T cells are self-restricted meaning they bind foreign antigens only when presented on MHCs.  T cells are self-tolerant meaning that T cells will not be activated by self-antigens.

Lymphoid progenitors (immature T cells) migrate from the bone marrow to the thymic cortex. Here they develop through a number of intermediate stages termed double-negative (DN) 1 to 4 where the cells remain negative for both the CD4 and CD8 co-receptors. Between DN1-4, the immature T cells that express unique and functional TCR are nurtured, while those that do not undergo apoptosis ('death by neglect'). T cells then express both CD4 and CD8 receptors becoming double positive (DP) and go through a process called Positive Selection. In positive selection DP T cells are exposed to cortical thymic epithelial cells (cTEC) that are displaying self-antigens on MHC-I and MHC-II. DP T cells that preferentially bind to the MHC-I complex will then repress CD4 expression and express only CD8 receptors, becoming CD8+ SP (single positive) cells. Likewise, DP T cells that preferentially bind to the MHC-II complex will then repress CD8 expression and express only CD4 receptors, becoming CD4+ SP (single positive) cells. These CD4+ and CD8+ cells migrate into the medulla of the thymus where they undergo negative selection. In this process, both medullary TEC (mTEC) and APCs display a large array of self peptides on their MHC molecules. T cells that bind strongly to the self-antigen will undergo apoptosis. T cells that bind weakly will become Effector Cells (either CD8+ Cytotoxic T cells or CD4+ Helper T cells). T cell that bind moderately will become Regulatory T cells.
Lymphoid progenitors (immature T cells) migrate from the bone marrow to the thymic cortex. Here they develop through a number of intermediate stages termed double-negative (DN) 1 to 4 where the cells remain negative for both the CD4 and CD8 co-receptors. Between DN1-4, the immature T cells that express unique and functional TCR are nurtured, while those that do not undergo apoptosis (‘death by neglect’). T cells then express both CD4 and CD8 receptors becoming double positive (DP) and go through a process called Positive Selection. In positive selection DP T cells are exposed to cortical thymic epithelial cells (cTEC) that are displaying self-antigens on MHC-I and MHC-II. DP T cells that preferentially bind to the MHC-I complex will then repress CD4 expression and express only CD8 receptors, becoming CD8+ SP (single positive) cells. Likewise, DP T cells that preferentially bind to the MHC-II complex will then repress CD8 expression and express only CD4 receptors, becoming CD4+ SP (single positive) cells. These CD4+ and CD8+ cells migrate into the medulla of the thymus where they undergo negative selection. In this process, both medullary TEC (mTEC) and APCs display a large array of self peptides on their MHC molecules. T cells that bind strongly to the self-antigen will undergo apoptosis. T cells that bind weakly will become Effector Cells (either CD8+ Cytotoxic T cells or CD4+ Helper T cells). T cell that bind moderately will become Regulatory T cells.

B Cell Development and Selection

B cell development is similar to T cell development, in that B cells arise in the bone marrow from hemopoietic stem cells and through somatic recombination each develop a unique B cell receptor (BCR).  The B cells then undergo both positive and negative selection, ensuring that: (1) BCRs are functional and that (2) B cells do not bind to self-antigens.  B cells that either lack a functioning BCR or bind to self-antigens are induced to undergo apoptosis.  The surviving B cells travel to the spleen, mature into self-tolerant naïve B cells that then migrate to and populate lymphatic tissues.

 

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