T‐cell receptor proximal signaling via the Src‐family kinases, Lck and Fyn, influences T‐cell activation, differentiation, and tolerance

  title={T‐cell receptor proximal signaling via the Src‐family kinases, Lck and Fyn, influences T‐cell activation, differentiation, and tolerance},
  author={Robert J. Salmond and A. M. Iliana Filby and Ihjaaz Qureshi and Stefano Caserta and Rose Zamoyska},
  journal={Immunological Reviews},
Summary:  T‐cell development in the thymus and activation of mature T cells in secondary lymphoid organs requires the ability of cells to respond appropriately to environmental signals at multiple stages of their development. The process of thymocyte selection insures a functional T‐cell repertoire, while activation of naive peripheral T cells induces proliferation, gain of effector function, and, ultimately, long‐lived T‐cell memory. The T‐cell immune response is initiated upon engagement of… 

[Function of the Lck and Fyn in T cell development].

Both Lck and Fyn are required for each of these TCR-based signaling pathways, and Lck seems to be the major contributor, while Fyn can only supplement some functions of Lck.

T Cells + Antigen-Experienced CD8 Kinase between Naive and Differential Polarization of C-Terminal Src

There is differential redistribution of a key negative regulator away from the site of TCR engagement in Ag-experienced CD8 + T cells, which might be associated with the more efficient responses of these cells on re-exposure to Ag.

Primary T cell immunodeficiencies associated with disturbed proximal T cell receptor signalling caused by human autosomal recessive LCK, ZAP-70 and ITK-mutations

This doctoral thesis provides detailed clinical, immunological and biochemical analyses especially of TCR:CD3:ζ-signalling and compares the findings to the well-established Lck-/-, Zap-70-/- and Itk-/- murine models.

Differential Polarization of C-Terminal Src Kinase between Naive and Antigen-Experienced CD8+ T Cells

There is differential redistribution of a key negative regulator away from the site of TCR engagement in Ag-experienced CD8+ T cells, which might be associated with the more efficient responses of these cells on re-exposure to Ag.

T Cell Receptor Signal Initiation Induced by Low-Grade Stimulation Requires the Cooperation of LAT in Human T Cells

The results indicate for the first time that LAT promotes TCR signal initiation and suggest that this adaptor may contribute to maintain active Lck in proximity of their substrates.

IL-12 Signals through the TCR To Support CD8 Innate Immune Responses

It is shown that IL-12 and other proinflammatory cytokines transduce signals through the TCR signalosome in a manner that requires Fyn activity and self-peptide–MHC (self-pMHC) interactions, which is crucial for CD8 innate T cell functions.

The T cell receptor‐mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems

The mechanism for the T CR‐induced phosphorylation of specific sites on Pyk2 is defined more fully, suggesting that the TCR has a distinct pathway for the activation of Pyk 2 compared with other receptor systems.

Cooperation between T cell receptor and Toll-like receptor 5 signaling for CD4+ T cell activation

The merged model accurately predicted the experimental results, showing that the activation of TLR5 can play a similar role to that of CD28 activation with respect to AP-1, CREB, and NF-κB activation, thereby providing insights regarding the cross-regulation of these pathways in CD4+ T cells.

Src-family kinases negatively regulate NFAT signaling in resting human T cells

A novel role ofSFKs is identified in preventing aberrant NFAT1 activation in resting T cells, and it is suggested that maintaining this pool of active SFKs in therapeutic T cells may increase the efficacy of T cell therapies.



The influence of the src‐family kinases, Lck and Fyn, on T cell differentiation, survival and activation

Recent experiments addressing how these two src‐kinase family members interface with downstream signaling pathways to regulate these diverse aspects of T cell behavior are discussed.

Hypophosphorylated TCR/CD3ζ signals through a Grb2‐SOS1‐Ras pathway in Lck knockdown cells

The recruitment of Grb2‐SOS1 to CD3ζ of the TCR complex after prolonged anti‐CD3 (OKT3) stimulation in T cells with Lck knockdown is reported, indicating that alternative Lck‐independent pathways of T cell activation exist or that low levels of Lck elicit other signals than normal T cellactivation.

Aberrant TCR-mediated signaling in CD45-null thymocytes involves dysfunctional regulation of Lck, Fyn, TCR-zeta, and ZAP-70.

Molecular analysis suggests that the threshold for TCR signal transduction is greatly increased in CD45-null T cells, thus explaining the profound defects in thymic development.

The Lck SH3 Domain Is Required for Activation of the Mitogen-activated Protein Kinase Pathway but Not the Initiation of T-cell Antigen Receptor Signaling*

It is demonstrated that Lck has a role in the activation of signaling pathways beyond the initiation of TCR signaling and suggested that the MAPK pathway may be selectively controlled by regulating the function of Lck.

Differential association of protein tyrosine kinases with the T cell receptor is linked to the induction of anergy and its prevention by B7 family-mediated costimulation

The data suggest that the induction of anergy is an active signaling process characterized by the association of TCR zeta and fyn, and strategies to inhibit or activate TCR-associated, specific protein tyrosine kinase-mediated pathways may provide a basis for drug development with potential applications in the fields of transplantation, autoimmunity, and tumor immunity.

Differential T-Cell Antigen Receptor Signaling Mediated by the Src Family Kinases Lck and Fyn

The ability of Fyn to mediate TCR signal transduction in an Lck-deficient T-cell line (JCaM1) is examined, indicating that Fyn mediates an alternative form of TCR signaling which is independent of ZAP-70 activation and generates a distinct cellular phenotype.

Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

Animal models and cell line studies both indicate a critical role for Lck and Fyn in proximal T-cell antigen receptor (TCR) signal transduction, and SFKs are required for each of these TCR-based signals, and Lck seems to be the major contributor.

Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor

It is shown that agonists cause association of active lck and active ZAP-70 with p120-GTPase–activating protein (p 120-GAP), supporting a kinetic, CD4-dependent model for the mechanism of action of variant TCR ligands.

CD45 tyrosine phosphatase‐activated p59fyn couples the T cell antigen receptor to pathways of diacylglycerol production, protein kinase C activation and calcium influx.

Results indicate that CD45‐regulated p59fyn plays a critical role in coupling the TCR to specific intracellular signalling pathways and that CD4‐ or CD8‐p56lck can only restore signal transduction coupling inCD45‐ cells when brought into close association with the T CR.