Fiche #196

Naïve T cell activation by DCs [#xxx] requires three signals, termed signal-1, -2 and -3.

Naïve T cell activation by DCs [#xxx] requires three signals, termed signal-1, -2 and -3. The reactivation of effector or memory T cells is rather signal 2 independent, ensuring rapid execution of effector function at sites of inflammation independent of APCs.

Naïve T cell activation by DCs [#xxx] requires three signals, termed signal-1, -2 and -3.

Signal-1 is equivalent to the binding of TCR to peptide-MHC complex

Signal-2 requires the interaction of costimulatory molecules at the interface between DCs and T cells (CD80-CD86/CD28; CD40/CD40L)

By secreting cytokines, DCs promote naïve T cells differentiate into Th1, Th2, Th17 [#xxx], or Treg cells in a stimulus-dependent manner.

Signal 1 leads to phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) on CD3 [#xxx], which is closely adjacent to TCR by Lck kinase. T cells receive signal-1 when the activation cascade leads to signaling through multiple TCR for several hours. This sustained signaling is necessary for the effective activation of signal transduction pathways that lead to the activation of nuclear transcription factors.

The activation signal of these costimulatory molecules [#xxx] is delivered to T cells via the ITAM of the cytoplasmic domain, which enhances the TCR response to antigen. CD28/CD80 signal activate T cells to express multiple other costimulatory molecules, these costimulatory molecules control the balance of immune response. Negative signals, such as CTLA-4/CD80 and CTLA-4/CD86 have been identified

CD4+ T lymphocytes can be grouped into subsets known as Th1, Th2, Th3, Th9, Th17, Treg, Tr1, and Tfh. Th1 cells [#xxx] require extrinsic IL-12 and IFNγ to express T-bet and IFNγ. Th2 cells [#xxx] require extrinsic IL-4 and are stabilized by IL-2 to express GATA3, IL-4, IL-5, and -IL13. Th3 cells [#xxx] require extrinsic TGFβ and express TGFβ. Th17 cells require extrinsic TGFβ and IL-6, IL-21 or IL-23 to express RORγt and produceIL-21, IL-17A, and IL-17F. Treg cells require extrinsic TGFβ and IL-2, they express Foxp3, TGFβ and in some cases IL-10. Tr1 cells require extrinsic IL10, expressing IL10 .Tfh cells require IL-21, they express Bcl6.

TCR engagement can trigger distinct functional outputs depending upon the affinity [#xxx] of the TCR–pMHC interaction. TCR signalling also plays a critical role in the lineage specification and development of specialized T cell subsets

For entire T cell activation a costimulatory signal (signal 2) is mandatory, as a T cell receptor signal in absence of costimulation renders respective T cells anergic

Detection of mature DCs [#xxx] producing large quantities of inflammatory cytokines strongly supports the notion that DCs play a key role in autoimmune diseases by promoting a deleterious imbalance between Th1, Th2, and Th17 cells

Activation-induced cell death (AICD) [#xxx] occurs as a consequence of repeated stimulation through the CD3/TCR (T cell receptor) of the T cells.

Pattern of costimulation is a central feature distinguishing tolerogenic and immunogenic DC.

Cytokine deprivation induces apoptosis of activated T cells. In opposite, Cytokine release syndrome (CRS) is a systemic inflammatory response that can be triggered by a variety of factors such as infections or immunotherapy. CRS is caused by a large, rapid release of cytokines into the blood from immune cells.

Infection of DC and interaction with their APC function by downregulation of costimulatory molecules may represent a rather common mechanism by which viruses establish persistent infection.

The cytokines may also dictate the conversion of T cell in a different subset. Multiple studies report the transit of Treg cells toward Th17 cells in response to the addition of exogenous IL-6 in the presence of TGFβ.

Treatment of T cells with monoclonal [#xxx] anti-CD3 antibodies and anti-CD28 antibodies provide a co-stimulatory signal that engages the TCR which can be used for antigen-induced activation.

Immunogenic DC are currently applied in various clinical studies to evoke anti-tumor immunity in cancer patients.

Cytokine-based immunotherapy [#xxx] is a promising field in the cancer treatment, since cytokines, as proteins of the immune system, are able to modulate the host immune response toward cancer cell, as well as directly induce tumor cell death.

Anti-CD3 monoclonal antibodies are an immunosuppressant and can induce anergy and apoptosis of activated T cells. Muromonab-CD3 is a murine IgG2, which specifically binds to CD3 on T cells and blocks proliferation and function of T cells.

Treatment of T cells with monoclonal anti-CD3 antibodies and anti-CD28 antibodies provide a co-stimulatory signal that engages the TCR which can be used for antigen-induced activation.

IL-2 was the first cytokine found to have therapeutic benefit and was initially proposed in patients with advanced metastatic renal cell cancer and melanoma. IL-7-based therapies was evaluated to restore immune function in immunocompromised individuals, such as those with HIV and the aged, and to enhance the activity of vaccines and other cancer immunotherapies. IL-15 that increases growth and activity of T and NK cells is investigated to enhance the effectiveness of thertapeutic vaccines.

Engineered T cell receptors (TCRs) are recent therapeutic manufactured receptors of T cells which are used in adoptive T-cell immunotherapy [#xxx].

Abatacept (CTLA-4Ig) [#xxx] prevents complement fixation and modulates the necessary co-stimulatory signal for T cell activation. Abatacept is mainly used in Rhumatoïd Arthritis treatment.

Immunosuppressive cytokines can be employed to therapeutically dampen hyperactive immune responses (e.g., cytokine release syndrome), to promote tissue regeneration, or to counteract autoimmune or inflammatory disease pathologies (e.g., rheumatoid arthritis and systemic lupus erythematosus)