Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4
            <sup>+</sup>
            T Cells

Li, Wei; Whaley, Carmella D.; Mondino, Anna; Mueller, Daniel L.

doi:10.1126/science.271.5253.1272

Cited by 422 publications

(296 citation statements)

References 45 publications

Supporting

Mentioning

272

Contrasting

Unclassified

Order By: Relevance

“…The cell divisionassociated hyporesponsive state that we observe also shares similarities with clonal anergy at the molecular level. Similar to the undivided CD4 ϩ T cells described in this work, both mouse and human T cell clones rendered anergic by TCR engagement in the absence of CD28 costimulation exhibit a normal increase in intracellular calcium following TCR engagement (15), but suffer from quantitative defects in Ras-coupled MAPK activation (22)(23)(24)(25). Also, the cyclin-dependent kinase inhibitor p27 kip1 , which we show is highly elevated in the CD4 ϩ T cells that fail to divide after activation, has recently been shown to function as a molecular anergy factor in human T cell clones stimulated in the absence of CD28 costimulation (65).…”

Section: Discussionmentioning

confidence: 84%

“…Therefore, we find that CD4 ϩ T cells that fail to proliferate in response to primary stimulation suffer from a quantitative defect in TCR-coupled activation of the Ras-Raf-MAPK pathway. This signaling defect has been described previously in anergic T cell clones (22)(23)(24)(25), and could explain the inability of the undivided cells to produce IL-2.…”

Section: The Integrity Of Tcr-coupled Ras-raf-mitogen-activated Protementioning

confidence: 87%

See 1 more Smart Citation

T Cell Effector Function and Anergy Avoidance Are Quantitatively Linked to Cell Division

Wells

Walsh

Sankaran

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

We have shown previously that T cells activated by optimal TCR and CD28 ligation exhibit marked proliferative heterogeneity, and ∼40% of these activated cells fail entirely to participate in clonal expansion. To address how prior cell division influences the subsequent function of primary T cells at the single cell level, primary CD4+ T cells were subjected to polyclonal stimulation, sorted based on the number of cell divisions they had undergone, and restimulated by ligation of TCR/CD28. We find that individual CD4+ T cells exhibit distinct secondary response patterns that depend upon their prior division history, such that cells that undergo more rounds of division show incrementally greater IL-2 production and proliferation in response to restimulation. CD4+ T cells that fail to divide after activation exist in a profoundly hyporesponsive state that is refractory to both TCR/CD28-mediated and IL-2R-mediated proliferative signals. We find that this anergic state is associated with defects in both TCR-coupled activation of the p42/44 mitogen-activated protein kinase (extracellular signal-related kinase 1/2) and IL-2-mediated down-regulation of the cell cycle inhibitor p27kip1. However, these defects are selective, as TCR-mediated intracellular calcium flux and IL-2R-coupled STAT5 activation remain intact in these cells. Therefore, the process of cell division or cell cycle progression plays an integral role in anergy avoidance in primary T cells, and may represent a driving force in the formation of the effector/memory T cell pool.

show abstract

Section: Discussionmentioning

confidence: 84%

Section: The Integrity Of Tcr-coupled Ras-raf-mitogen-activated Protementioning

confidence: 87%

T Cell Effector Function and Anergy Avoidance Are Quantitatively Linked to Cell Division

Wells

Walsh

Sankaran

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Accumulating data show that interference with the Ras/ERK pathway using dominant negative Ras and catalytically inactive MEK1 transgenes inhibited positive selection (11). In addition, T cell clones rendered anergic and unable to produce IL-2 were shown to have defective MEK signaling (27).…”

Section: Discussionmentioning

confidence: 99%

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Ben-David¹,

Aruna²,

Seger

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are T cell-dependent antibody-mediated autoimmune diseases. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogues of two myasthenogenic peptides, p195-212 and p259 -271, down-regulated in vitro and in vivo MG-associated autoreactive responses. The dual APL was shown to exert its beneficial effects by up-regulating ERK1,2 in CD4 ؉ CD25 ؉ regulatory cells. In this study, we investigated a novel 50-kDa ERK-like protein (ERK-50) that is up-regulated significantly in addition to ERK1,2 after treatment with the dual APL. We report here that ERK-50 was upregulated in LN cells and in LN-derived T cells of mice that were immunized with the myasthenogenic peptides and treated with the dual APL. Moreover, ERK-50 was up-regulated in dual-APLtreated mice that were immunized with the Torpedo acetylcholine receptor. ERK-50 was demonstrated to be recognized by antibodies directed against the C and N termini of ERK1, against the C terminus of ERK2, and against general ERK. The 50-kDa ERK was shown to be stimulated by Con A, and inhibition of MEK1 down-regulated the 50-kDa ERK as was shown for ERK1,2. However, 4␤-phorbol 12-myristate 13-acetate (TPA) did not stimulate ERK-50. Finally, the activated ERK-50 was up-regulated in the dual-APL-induced CD4 ؉ CD25 ؉ regulatory cells. Thus, ERK-50 is suggested to be a novel ERK isoform, being up-regulated in response to treatment with the dual APL.autoimmunity ͉ immunomodulation ͉ kinase

show abstract

“…This pattern is distinct from the T cell clonal anergy model originally described for CD4 ϩ T cell lines and clones. In that model, activation of the RAS/MAPK pathway was shown to be strongly impaired, but the calcium/NFAT pathway was not (37)(38)(39). As seen in Fig.…”

Section: Early Signaling Events Are Marginally Affected In Clonally Amentioning

confidence: 99%

Adaptive Tolerance and Clonal Anergy Are Distinct Biochemical States

Chiodetti

Choi

Barber

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

Adaptive tolerance is a process by which T cells become desensitized when Ag stimulation persists following an initial immune response in vivo. To examine the biochemical changes in TCR signaling present in this state, we used a mouse model in which Rag2−/− TCR-transgenic CD4+ T cells were transferred into CD3ε−/− recipients expressing their cognate Ag. Compared with naive T cells, adaptively tolerant T cells had normal levels of TCR and slightly increased levels of CD4. Following activation with anti-TCR and anti-CD4 mAbs, the predominant signaling block in the tolerant cells was at the level of Zap70 kinase activity, which was decreased 75% in vitro. Phosphorylations of the Zap70 substrates (linker of activated T cells and phospholipase Cγ1 were also profoundly diminished. This proximal defect impacted mostly on the calcium/NFAT and NF-κB pathways, with only a modest decrease in ERK1/2 phosphorylation. This state was contrasted with T cell clonal anergy in which the RAS/MAPK pathway was preferentially impaired and there was much less inhibition of Zap70 kinase activity. Both hyporesponsive states manifested a block in IκB degradation. These results demonstrate that T cell adaptive tolerance and clonal anergy are distinct biochemical states, possibly providing T cells with two molecular mechanisms to curtail responsiveness in different biological circumstances.

show abstract

Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4 ⁺ T Cells

Cited by 422 publications

References 45 publications

T Cell Effector Function and Anergy Avoidance Are Quantitatively Linked to Cell Division

T Cell Effector Function and Anergy Avoidance Are Quantitatively Linked to Cell Division

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Adaptive Tolerance and Clonal Anergy Are Distinct Biochemical States

Contact Info

Product

Resources

About

Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4 + T Cells

Cited by 422 publications

References 45 publications

T Cell Effector Function and Anergy Avoidance Are Quantitatively Linked to Cell Division

T Cell Effector Function and Anergy Avoidance Are Quantitatively Linked to Cell Division

A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses

Adaptive Tolerance and Clonal Anergy Are Distinct Biochemical States

Contact Info

Product

Resources

About

Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4 ⁺ T Cells