T Cell Activation

See also T cell priming by DCs    See also TH (CD4+) cell activation See also cluster of differentiation molecules

Several factors are thought to influence the fate of T cells after encounter with antigen, including the strenght of the signal delivered after TCR triggering, the balance of prolinflammatory versus antiinflammatory cytokines present at the time of T cell encounter with antigen, and the intergrated signals delivered by costimulatory molecules present on the T cell surface after intereaction with their ligands on APCS.

T cell activation involves ligation of a series of adhesion molecules starting with an antigen to its specific T cell receptor (TCR)/cluster of differentiation (CD) complex, expressed on the surface of the T cell. In order for the activation to proceed, additional costimulatory signals, such as ligation of the CD28/B7, CD4/HLA class II and CD/HLA class I antigens are required. During the activation process, the lymphoctye begins to acquire new CD molecules such as CD25 (IL-2R), CD69, CD71 and HLA-DR. This is accompanied by an increase of cytokines production by the primed T cells. The cytokines are essential for the differentiation, proliferation and amplification of the T cells. The most important of which is IL-2. Costimulation molecules are necessary not only for naive T cell clonal expansion but also for memory T cell clonal expansion.

The priming of T cell responses requires conjugate formation between DCs and T cells. During the 1st 8 hours after entry from the circulation, T cells and DCs undergo multiple short encounters. Long-lasting, stable ineractions of at least 30 minutes duration occur during the subsequent 12 hours, during which production of IL-2 and IFNγ by T cells is initiated. Afer 26 hours, T cells again have short encounters with DCs, now accompanied by the onset of proliferation and rapid migration.

The Two Signal Model of T cell Activation

Signal 1: is recognition of peptide/MHC complexes by the TCR. For CD4 cells (class II MHC/CD4). For CD8 cells (class I MHC/CD8).

Signal 2: Interaction between T cell membrane receptors and APC membrane ligands. This second signal can involve 2 events. First, adhesion which stabilizes or strenghtens APC-T cell intereaction and second, costimulation which provides additive or synergistic signals to those from TCR recognition of peptide/MHC. There are multiple membrane receptors that can positively signal and potentially contribute to signal 2 including molecules from the TNFR superfamily, cytokine receptors and Ig superfamily. There are also multiple membrane receptors that can negatively signal and potential suppress the generation of signal 2 from these families.

It is believe that there is a balance of positive and negative signals which determines the response. One reason there may be multiple molecules involved is for differential expression of the molecules. Positive signals can activate, expand, differentiate, lead to survival and cytokine production and include:

Positive and Negative Signals from Costimulatory Molecules

Antigen-specific activation and proliferation of lymphocytes are regualted by both positive and negative signals from costimulatory molecules. The most extensively characterized T cell costimulatory pathway is B7-CD28, in which B7-1 (CD80) and B7-2 (CD86) can each engage two receptors, the stimulatory CD28 and the inhibitory CTLA-4 (CD152). In conjunction with signaling through the T cell receptor, CD28 ligation increases antigen specific proliferation of T cells, enhances production of cytokines, stimulates differentiation and effector function and promotes survival of T cells. In contrast, signaling through CTLA-4 is thought to deliver a negative signal that inhibits T cell prolfieration, IL-2 production and cell cycle progression.

After signalling through the T cell receptor, ligation of CD28 and transduction of a costimulatory signal induces T cells to proliferate and secrete IL-2. CTLA4 is homologous to CD28 but is not expressed on resting T cells and appears following T cell activation. CTLA4 appears to be critical in negative regulation of T cells responses.

In addition to B71 and B7-2, there are other antigens on the surface of antigen presenting cells which modulate costimulation of immune cells. For example, B7-4 polypeptides have been isolated from keratinocyte and placental cDNA libraries. B7-4 has also been found to costimulate or inhibit T cells. PD-1 (in a family of inhibitory receptors with CTLA4) is a receptor for B7-4.

Positive and Negative Regulators of the Ig Superfamily:

Positive regulators

CD28 is the best characterized T cell costimulatory receptor. Its two ligands are CD80 (B7-1) and CD86 (B7-2) (on DCs CD86 is the most critical molecule for amplification of T cell responses) which are expressed on APCs such as dendritic cells. Transiently blocking CD28-B7 costimulation using either monoconal antibodies or CTLA4Ig (a soluble receptor-immunoglobulin fusion protein that binds CD80 and CD86 with higher affinity than CD28) prolongs allograft survival in rodent models and in some instances induces tolerance).

CD28 delivers a positive costimulatory signal, enhancing the production of certain lymphokines such as IL-2 via transcriptional and postranscriptional mechanisms.

ICOS-B7RP1

Negative regulators

CTLA4 which is expressed a few days after T cell activation, delivers a counterregulatory negative signal that antagonizes CD28 cell activation.

PD-1: is a receptor implicated in negative regulation of T and B cell functions. Its ligands are B7-H1 and B6-CD which also costimulate T cell responses.

Barber et al. have reported that exhausted T cells of mice can be revived by treatment with an antibody that blocks the itneraction between the PD-1 receptor and its ligand PD-L1. This group noted that although the early functtional T cells in acute or chronic infections make a lot of PD-1, after clearance of the acute infection the resting memory cells lose epression of this marker. In chronically infected animals, however, the T cells retain high levels of PD-1 expression. In addition, one of the ligands for this receptor, PD-L1, is expressed at high levels on the surface of chronically infected cells This receptor-ligand system has been postulated to inhibit signalling through the T-cell antigen receptor-the receptor that triggers the response to a pathogen.

BTLA, CD200R. Negative regulators recruit phosphatases (PP2A, SHP-1/2, PTEN).

Positive and Negative Regulators of the TNFR/TNF family:

Positive regulators

CD40L-CD40,

CD27-CD70

RANKL-RANK

Negative regulators include

Fas-FasL

Positive and Negative Cytokine regulators: TNFRII-TNF

Negative regulators include

IL-10R-IL10

The immunological synapse focuses Ag and costimulatory molecules. CD28/B7 is critical for formation of the synapse.

Recipricol Co-stimulationActivation by T cells

Costimulatory ligands on APC are largely inducible by CD40: Many of the costimulatory ligands are not expressed only have CD40-CD40L interaction. (TLRs can also induce many of these costimulatory ligands).

The above looks mainly at costimulatory molecule effect on T cells, how about effect on APC themselves? As an example, B7-1 can induce IFNy production through a DC due to CTLA4.

Notch Ligand-Receptors as Costimulatory Molecules: Some papers suggest these molecules might regulate Th differentiation into either Th1/Th2.

Signal Transduction Pathways Required for T cell activation:

The nature and location of the sustained signal transduciton pathways required for T cell activation are unknown. However, production of phosphatidylinositol (3,4,5) triphosphate (PIP3) has been reported to be sustained for hours as T cells respond to antigen. In addition, sustained elevation of PIP3 was essential for T cell proliferation.