T cell activation

Dendritic
cell

HLA molecules

T cells

TCR

Cytokines

Secondary
lymphoid
organs

Where?

In the T cell zone of the secondary lymphoid organs, which constitutes a zone of concentration of antigens:

• In the lymph nodes : the paracortex (also called the cortico-medullary junction)

Organisation of a lymph node

• In the spleen : in the white pulp, in the Periarteriolar Lymphoid Sheats (PALS)

Organisation of the white pulp of the spleen

When?

After undergoing positive and negative selection in the thymus eliminating ineffective and self-reactive clones respectively (see T cell ontogeny), T cells circulate in the bloodstream and enter secondary lymphoid organs.

They scout the dendritic cells, guided by the network of reticular fibroblastic cells. If a T cell recognises the complex [HLA-peptide molecule] corresponding to its TCR on the surface of a dendritic cell, this constitutes its first activation signal.

How is this done?

The activation of naive T cells can only be done by dendritic cells.

Three activation signals are necessary to activate the T cell.

This recognition is stabilised by the interaction of CD4 or CD8 of the T cell with the HLA molecule of the dendritic cell, Class II or I, respectively. Following this interaction, CD3 associated with the TCR transduces a signal via the ITAM motifs present intracellularly.

This interaction amplifies and complements the intracellular activation signals from the [TCR-CD3] complex, which will allow the secretion of IL-2 by the dendritic cell and the expression of an IL-2R receptor by the T cell. Without this second signal and IL-2, the T cell would be anergic.

Cytokines are secreted mainly by dendritic cells, but also by other cells in the microenvironment. They allow the functional differentiation of lymphocytes into cytotoxic T cells for CD8+ T cells or helper T cells for CD4+ T cells, as well as the initiation of clonal proliferation.

To escape the interaction with the dendritic cell, the T cell expresses after 2 to 3 days the CTLA-4 molecule (Cytotoxic T Lymphocyte Antigen 4, or CD152), which is more affinity for the CD80 and CD86 molecules than the CD28.

Unlike the interaction [CD28-CD80/86], the interaction [CTLA-4-CD80/86] does not generate an activation signal to the T cell. The CTLA-4 expression will therefore stop the interaction with the dendritic cell , which allows the T cell to:

• either leave the secondary lymphoid organ to proliferate into functional clones directed against the antigen;
• or head towards the T/B interface zone of the secondary lymphoid organs to contribute to the activation of B cells.

The activation of T cells will lead to a clonal expansion , which increases 1,000 to 10,000 times the number of T cells specific for the complex [HLA-peptide molecule] initiating this activation. The vast majority of activated T cells leave the secondary lymphoid organs to exert their effector actions in the tissues, towards the cells which present the same complex [HLA-peptide molecule] on their surface.

The effector functions of T cells are mainly:

Two cytotoxicity mechanisms are used by CD8+ T cells :

• exocytosis of lytic granules
  For example, perforin (membrane permeabilisation molecule) and granzymes (proteases), which lead to cell lysis after destruction of the membrane.
• expression of cell death receptor ligands
  CD8+ T cells constitutively express cell death ligands
  (e.g., TNF-α and TRAIL), whose receptors are expressed by the target cell.

The previously activated CD4+ T cell interacts with the B cell to allow it to fully activate after it has recognised an antigen via its BCR:
It is the T/B-cell cooperation (see B cell activation).

CD4+ T cells also integrate signals from the environment, and respond to them by in turn synthesising cytokines, which will guide the immune response.
Depending on the cytokines that the lymphocyte secretes, we distinguish different profiles, the best known of which are the Th1, Th2, and Th17 profiles.
CD4+ T cell profiles will not be further covered here.

* These substances have a more marked cytostatic effect on lymphocytes than on other cells due to the dependence of T and B cells on the de novo synthesis of purines, while other cell types can use supplementary metabolic pathways.