Thymic Positive Selection and Adaptive Immune Activation Mechanisms

Posted on Feb 28, 2026 in Biomedical Sciences

Positive Selection in the Thymus

Positive selection occurs in the corticomedullary area of the thymus to select T lymphocytes capable of recognizing self HLA molecules.

Stages:

  1. Epithelial cells in this area are antigen-presenting cells (APCs) and express abundant HLA-I and HLA-II with their own peptides.
  2. The new T cells, with their T cell receptor (TCR), examine the APC.
    • If the TCR of the T cell binds to the HLA molecule of the APC, the T cell survives because it receives survival signals.
    • If the TCR of the T cell does not bind to the HLA molecules, the T cell dies by apoptosis or is abandoned, since it does not receive survival signals.
  4. Selected lymphocytes differentiate into CD4 or CD8 T cells. Before binding to the APC, T lymphocytes are double positive (CD4+ and CD8+). After selection, they become single positive, expressing only one coreceptor:
    • If the TCR binds HLA-I, the CD8 coreceptor is selected.

Four Stages of CD4 T Cell Activation

Four stages of CD4 T cell activation:

  1. Recognition phase
  2. Activation phase
  3. Clonal expansion
  4. Differentiation into effector T cells

Activation Phase and Two-Signal Requirement

The activation phase takes place in the paracortex during the immunological synapse between dendritic cells (DCs) and naïve CD4 T lymphocytes and requires two signals.

1st signal: Produced by the binding of the TCR on the T cell to the specific antigen presented by HLA molecules on DCs.

2nd signal: Provided by co-stimulatory molecules, mainly CD80 or CD86 on DCs, which bind to CD28 on the T cell. This second signal depends on recognition of PAMPs by DCs through PRRs, which induces DC maturation and increased expression of HLA and co-stimulatory molecules.

Both signals are essential. If antigen recognition occurs without co-stimulation, the T cell becomes anergic, ensuring tolerance to self antigens, since DCs presenting self antigens usually lack co-stimulatory molecules.

B Cell Activation: Location and Objective

Location: The 1st phase of B cell activation occurs in lymph nodes, initially in the follicles and later in the interfollicular region near the paracortex.

Objective: Clonal expansion, antibody secretion and differentiation into plasma cells, followed by memory B cell generation.

Requirements for B Cell Clonal Expansion

Soluble antigens reach the lymph node (MAC) and are recognized by B cell receptors (BCRs) on B cells. B cells internalize the antigen, process it, and present it via HLA-II, then migrate toward the interfollicular region. At the same time, DCs activate T cells, which differentiate into Tfh cells.

B cells are activated through a combination of:

  • Antigen presentation via HLA-II
  • Recognition by Tfh cells through the TCR
  • CD40–CD40L interaction

This induces extrafollicular clonal expansion and differentiation into plasma cells that mainly secrete IgM before memory acquisition.

Recognition of Intracellular Cytoplasmic Pathogens

Intracellular cytosolic pathogens are detected by cytosolic PRRs located in the cytoplasm of innate immune cells, especially DCs and macrophages.

Recognition of intracellular PAMPs induces the production of type I interferons (IFN-α and IFN-β) and pro-inflammatory cytokines. Type I interferons induce an antiviral state in neighboring cells by inhibiting viral replication, degrading viral RNA, inhibiting translation, and increasing antigen presentation.

Plasmacytoid dendritic cells are major producers of type I interferons after viral recognition and strongly amplify the antiviral response.

Inflammation and interferons promote the activation and recruitment of NK cells. Activated NK cells induce cytotoxicity mechanisms depending on the balance between activating and inhibitory signals.

Conventional dendritic cells phagocytose apoptotic infected cells and migrate to lymph nodes to initiate the adaptive immune response.

Tolerogenic Vaccine Against an Allergen

A tolerogenic vaccine against an allergen must induce immune tolerance instead of an inflammatory immune response.

This type of response is achieved when DCs detect little or no PAMPs, which prevents their full maturation and the expression of co-stimulatory molecules. As a consequence, DCs secrete anti-inflammatory cytokines, especially TGF-β.

The presence of TGF-β promotes differentiation of naïve T lymphocytes into regulatory T cells (Treg) instead of effector T cells such as T helper 2 (Th2) cells, which are responsible for allergic responses.

Treg cells play a key role in tolerance because they inhibit DCs and effector T lymphocytes and can convert DCs into tolerogenic DCs.

As a result, this prevents exaggerated Th2 responses, mast cell activation, eosinophilia, and tissue damage associated with allergies.