CD8+ T Cell Responses to a Viral Escape Mutant Epitope: Active Suppression via Altered SHP-1 Activity

Schnell, Frederick J.; Alberts-Grill, Noah; Evavold, Brian D.

doi:10.4049/jimmunol.0801798

Cited by 12 publications

(14 citation statements)

References 47 publications

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“…Previously, we have shown that the negative regulator SHP-1 plays a role in controlling an autoimmune response to MOG [50], and in CD8+ T cells that the peak of SHP-1 activity occurs at 1 min in response to antigen [51]. Here, the kinetics of SHP-1 activity was analyzed following T cell activation.…”

Section: Resultsmentioning

confidence: 99%

Low 2-Dimensional CD4 T Cell Receptor Affinity for Myelin Sets in Motion Delayed Response Kinetics

et al. 2012

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T cells recognizing self-peptides that mediate autoimmune disease and those that are responsible for efficacious immunity against pathogens may differ in affinity for antigen due to central and peripheral tolerance mechanisms. Here we utilize prototypical self-reactive (myelin) and viral-specific (LCMV) T cells from T cell receptor (TCR) transgenic mice (2D2 and SMARTA, respectively) to explore affinity differences. The T cells responsive to virus possessed >10,000 fold higher 2D affinity as compared to the self-reactive T cells. Despite their dramatically lower affinity for their cognate ligand, 2D2 T cells respond with complete, albeit delayed, activation (proliferation and cytokine production). SMARTA activation occurs rapidly, achieving peak phosphorylation of p38 (1 minute), Erk (30 minutes), and Jun (3 hours) as well as CD69 and CD25 upregulation (3 and 6 hours, respectively), with a corresponding early initiation of proliferation. 2D2 stimulation with MOG results in altered signaling – no phospho-Erk or phospho-p38 accumulation, significantly delayed activation kinetics of Jun (12 hours), and delayed but sustained SHP-1 activity – as well as delayed CD69 and CD25 expression (12–24 hours), and slow initiation of proliferation. This delay was not intrinsic to the 2D2 T cells, as a more potent antigen with >100-fold increased 2D affinity restored rapid response kinetics in line with those identified for the viral antigen. Taken together, these data demonstrate that time can offset low TCR affinity to attain full activation and suggest a mechanism by which low affinity T cells participate in autoimmune disease.

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Section: Resultsmentioning

confidence: 99%

Low 2-Dimensional CD4 T Cell Receptor Affinity for Myelin Sets in Motion Delayed Response Kinetics

et al. 2012

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“…These data are consistent with previous findings that suggest that SHP-2 associates with the adaptor protein Gab2, leading to its membrane localization near the TCR and proximal tyrosine kinases (11). SHP-1 is the other SH2 domain–containing PTP that is proposed to regulate TCR-proximal signaling, but our previous study showed that SHP-1 is not a good target of TCR-induced ROS (24), although it is oxidized upon the stimulation of T cells by antigen-presenting cells (49). Thus, the current data suggest that SHP-2 is recruited to the membrane, where Duox1-dependent H 2 O 2 generation is prominent, and that it functions as a redox sensor that regulates proximal and distal TCR signaling events.…”

Section: Discussionmentioning

confidence: 99%

The Nonphagocytic NADPH Oxidase Duox1 Mediates a Positive Feedback Loop During T Cell Receptor Signaling

et al. 2010

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Production of reactive oxygen species, often by NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidases, plays a role in the signaling responses of cells to many receptor stimuli. Here, we describe the function of the calcium-dependent, nonphagocytic NADPH oxidase Duox1 in primary human CD4 + T cells and cultured T cell lines. Duox1 bound to inositol 1,4,5-trisphosphate receptor 1 and was required for early T cell receptor (TCR)-stimulated production of hydrogen peroxide (H 2 O 2 ) through a pathway that was dependent on TCR-proximal kinases. Transient or stable knockdown of Duox1 inhibited TCR signaling, especially phosphorylation of tyrosine-319 of ζ chain-associated protein kinase of 70 kilodaltons (ZAP-70), store-operated entry of calcium ions (Ca 2+ ), and activation of extracellular signal-regulated kinase. The production of cytokines was also inhibited by knockdown of Duox1. Duox1-mediated inactivation of Src homology 2 domain-containing protein tyrosine phosphatase 2 promoted the phosphorylation of ZAP-70 and its association with the Src family tyrosine kinase Lck and the CD3ζ chain of the TCR complex. Thus, we suggest that activation of Duox1, downstream of proximal TCR signals, generates H 2 O 2 that acts in a positive feedback loop to enhance and sustain further TCR signaling.

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“…Viral escape mutants or tumor antigens that have decreased affinity of peptide: MHC interaction can anergize reactive T cells [72–74]. Better understanding the mechanisms regulating the induction and maintenance of the anergic state may allow for therapeutic utilization of anergy as a means to treat autoimmune diseases or prevent graft rejection.…”

Section: Discussionmentioning

confidence: 99%

Destabilization of peptide:MHC interaction induces IL-2 resistant anergy in diabetogenic T cells

Edwards¹,

Evavold²

2013

Journal of Autoimmunity

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Autoreactive T cells are responsible for inducing several autoimmune diseases, including type 1 diabetes. We have developed a strategy to induce unresponsiveness in these cells by destabilizing the peptide:MHC ligand recognized by the T cell receptor. By introducing amino acid substitutions into the immunogenic peptide at residues that bind to the MHC, the half life of the peptide:MHC complex is severely reduced, thereby resulting in abortive T cell activation and anergy. By treating a monoclonal diabetogenic T cell population with an MHC variant peptide, the cells are rendered unresponsive to the wild type ligand, as measured by both proliferation and IL-2 production. Stimulation of T cells with MHC variant peptides results in minimal Erk1/2 phosphorylation or cell division. Variant peptide stimulation effectively initiates a signaling program dominated by sustained tyrosine phosphatase activity, including elevated SHP-1 activity. These negative signaling events result in an anergic phenotype in which the T cells are not competent to signal through the IL-2 receptor, as evidenced by a lack of phospho-Stat5 upregulation and proliferation, despite high expression of the IL-2 receptor. This unique negative signaling profile provides a novel means to shut down the anti-self response.

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CD8+ T Cell Responses to a Viral Escape Mutant Epitope: Active Suppression via Altered SHP-1 Activity

Cited by 12 publications

References 47 publications

Low 2-Dimensional CD4 T Cell Receptor Affinity for Myelin Sets in Motion Delayed Response Kinetics

Low 2-Dimensional CD4 T Cell Receptor Affinity for Myelin Sets in Motion Delayed Response Kinetics

The Nonphagocytic NADPH Oxidase Duox1 Mediates a Positive Feedback Loop During T Cell Receptor Signaling

Destabilization of peptide:MHC interaction induces IL-2 resistant anergy in diabetogenic T cells

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