Role of LAT in the Granule-Mediated Cytotoxicity of CD8 T Cells

Ou-Yang, Chih-wen; Zhu, Minghua; Fuller, Deirdre M.; Sullivan, Sarah; Chuck, Mariana; Ogden, Sarah; Li, Qi-Jing; Zhang, Weiguo

doi:10.1128/mcb.00356-12

Cited by 27 publications

(31 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These changes could reflect selection of particular T cell clones that occurs over the 4-week period in the LAT Y136F model with a diverse TCR repertoire. LAT protein turnover takes 4 days (Ou-Yang et al, 2012), therefore one week of tamoxifen treatment effectively results in 3 days of LAT NEG or LAT Y136F . In search of the immediate and direct effects of LAT perturbation in naïve CD4 T cells, we focused on this short period of LAT perturbation.…”

Section: Resultsmentioning

confidence: 99%

“…FasL is also a target of Egr transcription factors (Rengarajan et al, 2000) and we found Egr-1 , Egr-2 , and Egr-3 expressed at reduced levels in T cells with perturbed LAT function (Figure 2B). LAT Y136F T cells fail to upregulate FasL in response to TCR engagement (Ou-Yang et al, 2012; Sommers et al, 2002). The transcription factor Irf4 has received a lot of interest as a T cell fate-determining factor (Biswas et al, 2010; Huber and Lohoff, 2014).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

Summary CD4+ T cells differentiate into T helper cell subsets in feed-forward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naïve CD4+ T cells avoid spontaneous engagement of feed-forward mechanisms but retain a prepared state. T cells lacking the adapter molecule LAT demonstrate impaired TCR-induced signals yet cause a spontaneous lymphoproliferative T helper 2 (TH2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Here we demonstrate that tonic signals through LAT constitutively export the repressor HDAC7 from the nucleus of CD4+ T cells. Without such tonic signals, HDAC7 target genes Nur77 and Irf4 are repressed. We reveal that Nur77 suppresses CD4+ T cell proliferation and uncover a suppressive role for Irf4 in TH2 polarization; halving Irf4 gene-dosage leads to increases in GATA3+ and IL4+ cells. Our studies reveal that naïve CD4+ T cells are dynamically tuned by tonic LAT-HDAC7 signals.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cre-mediated deletion results in the expression of a non-functional LAT-GFP fusion protein, thus accurately marking T cells with the lat gene deleted (16). We crossed ERCreLAT f/f , OT-I TCR transgenic, and LAT −/− mice to generate ERCre + LAT f/− OT-Imice in which only one floxed allele needs to be deleted (17). With tamoxifen treatment, the lat gene can be inducibly deleted in OT-I cells in vivo .…”

Section: Resultsmentioning

confidence: 99%

The Requirement of Linker for Activation of T Cells in the Primary and Memory Responses of CD8 T Cells

Ou-Yang

Zhu

Sullivan

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Linker for activation of T cells (LAT) is a transmembrane adaptor protein that links T cell receptor (TCR) engagement to downstream signaling events. While it is clear that LAT is essential in thymocyte development and initiation of T cell activation, its function during T cell expansion, contraction, and memory formation remains unknown. To study the role of TCR-mediated signaling in CD8 T cells during the course of pathogen infection, we used an inducible mouse model to delete LAT in antigen-specific CD8 T cells at different stages of Listeria infection and analyzed the effect of deletion on T cell responses. Our data showed that LAT is important for maintaining CD8 T cell expansion during the priming phase; however, it is not required for CD8 T cell contraction and memory maintenance. Moreover, LAT deficiency accelerates memory differentiation during the effector-to-memory transition, leading to a higher frequency of KLRG1lowIL-7RhighCD62Lhigh memory T cells. Nonetheless, these LAT-deficient memory T cells were unable to proliferate or produce cytokines upon secondary infection. Our data demonstrated that, while it is dispensable for contraction and memory maintenance, TCR-mediated signaling regulates CD8 T cell memory differentiation and is essential for the memory response against pathogens.

show abstract

“…In addition, we found that blocking Tim-3 using the antagonistic antibody, 2E2, resulted in significantly more conjugates that had “stable” synapses. Initial proximal TCR signaling, such as Lck phosphorylation and subsequent downstream signaling to LAT, is required for stable synapse formation [41], further providing evidence that Tim-3 is involved in TCR proximal signaling. While the exact mechanism of how Tim-3 effects proximal signaling is still under investigation, our work provides preliminary evidence that Tim-3 may be involved in Lck regulation.…”

Section: Discussionmentioning

confidence: 99%

T Cell Ig and Mucin Domain–Containing Protein 3 Is Recruited to the Immune Synapse, Disrupts Stable Synapse Formation, and Associates with Receptor Phosphatases

Clayton

Haaland

Douglas-Vail

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

CD8+ cytotoxic T lymphocytes (CTL) are adept at killing virally infected cells and cancer cells and releasing cytokines (e.g. IFN-γ) to aid this response. However, during cancer and chronic viral infections, such as with Human Immunodeficiency Virus, this CTL response is progressively impaired due to a process called T-cell exhaustion. Previous work has shown that the glycoprotein, T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) plays a functional role in establishing T-cell exhaustion. Tim-3 is highly upregulated on virus and tumor antigen-specific CD8+ T-cells and antagonizing Tim-3 helps restore function of CD8+ T cells. However, very little is known of how Tim-3 signals in CTLs. In this study, we assessed the role of Tim-3 at the immunological synapse as well as its interaction with proximal TCR signaling molecules in primary human CD8+ T cells. Tim-3 was found withinCD8+T cell lipid rafts at the immunological synapse. Blocking Tim-3 resulted in a significantly greater number of stable synapses being formed between Tim-3hi CD8+T cells and target cells, suggesting that Tim-3 plays a functional role in synapse formation. Further, we confirmed that Tim-3 interacts with Lck, but not the phospho-active form of Lck. Finally, Tim-3 colocalizes with receptor phosphatases CD45 and CD148, an interaction that is enhanced in the presence of the Tim-3 ligand, galectin-9. Thus, Tim-3 interacts with multiple signaling molecules at the immunological synapse and characterizing these interactions could aid in the development of therapeutics to restore Tim-3-mediated immune dysfunction.

show abstract

Role of LAT in the Granule-Mediated Cytotoxicity of CD8 T Cells

Cited by 27 publications

References 39 publications

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

The Requirement of Linker for Activation of T Cells in the Primary and Memory Responses of CD8 T Cells

T Cell Ig and Mucin Domain–Containing Protein 3 Is Recruited to the Immune Synapse, Disrupts Stable Synapse Formation, and Associates with Receptor Phosphatases

Contact Info

Product

Resources

About