Duration of antigen receptor signaling determines T-cell tolerance or activation

Katzman, Shoshana D.; O’Gorman, William; Villarino, Alejandro V.; Gallo, Eugenio; Friedman, Rachel S.; Krummel, Matthew F.; Nolan, Garry P.; Abbas, Abul K.

doi:10.1073/pnas.1010560107

Cited by 62 publications

(63 citation statements)

References 22 publications

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“…In untreated sOVA-Tg mice, DO11.10 cells failed to produce high levels of cytokines, as previously reported (7,8,24) (Fig. 2A, 2B).…”

Section: Cd40 Activation Specifically Induces An Il-17 Responsesupporting

confidence: 61%

“…Additionally, the generation of Th1 and Th17 effector cells has been shown to be dependent on various other parameters including transcription factors, epigenetic modifications, and CD28 costimulation (2)(3)(4)(5). There is also evidence for temporal differences in the appearance of Th1 and Th17 cells, with most studies showing that the Th17 response peaks early, followed by the appearance of Th1 cells (6)(7)(8)(9). Finally, the development of these subsets is reciprocally regulated, due mainly to the fact that IFN-g is a powerful inhibitor of Th17 differentiation (3,10).…”

Section: Ifferent Subsets Of Effector Cd4mentioning

confidence: 99%

“…Interaction of these Ag-specific T cells with their cognate Ag in a lymphopenic host (sOVA-Tg/Rag 2/2 ) leads to a failure of tolerance, T cell activation, and a systemic inflammatory disease. During the propagation of this inflammatory disease there is uncontrolled activation of self-reactive DO11.10 cells, resulting in massive proliferation and the production of IFN-g and IL-17 (7)(8)(9). In the absence of B7 expression in the host, there is a failure to initiate an effector response from Ag-specific T cells, implying an essential contribution of B7 + APCs, presumably DCs, in the generation of cytokine-producing cells (15).…”

Section: Ifferent Subsets Of Effector Cd4mentioning

confidence: 99%

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Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

Katzman

Gallo

Hoyer

et al. 2011

The Journal of Immunology

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T cell–APC interactions are essential for the initiation of effector responses against foreign and self-antigens, but the role of these interactions in generating different populations of effector T cells in vivo remains unclear. Using a model of CD4+ T cell responses to a systemic self-antigen without adjuvants or infection, we demonstrate that activation of APCs augments Th17 responses much more than Th1 responses. Recognition of systemic Ag induces tolerance in self-reactive CD4+ T cells, but induction of CD40 signaling, even under tolerogenic conditions, results in a strong, Ag-specific IL-17 response without large numbers of IFN-γ–producing cells. Transfer of the same CD4+ T cells into lymphopenic recipients expressing the self-antigen results in uncontrolled production of IL-17, IFN-γ, and systemic inflammation. If the Ag-specific T cells lack CD40L, production of IL-17 but not IFN-γ is decreased, and the survival time of recipient mice is significantly increased. In addition, transient blockade of the initial MHC class II-dependent T cell–APC interaction results in a greater reduction of IL-17 than of IFN-γ production. These data suggest that Th17 differentiation is more sensitive to T cell interactions with APCs than is the Th1 response, and interrupting this interaction, specifically the CD40 pathway, may be key to controlling Th17-mediated autoimmunity.

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“…In untreated sOVA-Tg mice, DO11.10 cells failed to produce high levels of cytokines, as previously reported (7,8,24) (Fig. 2A, 2B).…”

Section: Cd40 Activation Specifically Induces An Il-17 Responsesupporting

confidence: 61%

Section: Ifferent Subsets Of Effector Cd4mentioning

confidence: 99%

Section: Ifferent Subsets Of Effector Cd4mentioning

confidence: 99%

See 1 more Smart Citation

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

Katzman

Gallo

Hoyer

et al. 2011

The Journal of Immunology

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“…Nonetheless, with the use of isotype antibody staining controls, our observation suggests that cytometric determination may be an invaluable predictor of phosphorylation levels of p56 lck that complements western blot analysis. Indeed our study is in line with previous phosflow protocols ( [41][42][43][44], as already described, mainly, for signaling molecules downstream of TCR-induced stimulation, including Stats, Akt, and S6 (45)(46)(47)(48). Here, in addition to demonstrating that pY416 antibody may be used for cytometric detection of pY394, we have demonstrated that TCR-induced stimulation of human primary T cells led to simultaneous phosphorylation of Y394 and Y505 residues.…”

Section: Discussionsupporting

confidence: 72%

TCR‐induced T cell activation leads to simultaneous phosphorylation at Y505 and Y394 of p56^lck residues

2012

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Biochemical studies have demonstrated that phosphorylation of lymphocyte cell kinase (p56 lck ) is crucial for activation of signaling cascades following T cell receptor (TCR) stimulation. However, whether phosphorylation/dephosphorylation of the activating or inhibitory tyrosine residues occurs upon activation is controversial. Recent advances in intracellular staining of phospho-epitopes and cytometric analysis, requiring few cells, have opened up novel avenues for the field of immunological signaling. Here, we assessed p56 lck phosphorylation, using a multiparameter flow-cytometric based detection method following T cell stimulation. Fixation and permeabilization in conjunction with zenon labeling technology and/or fluorescently labeled antibodies against total p56 lck or cognate phospho-tyrosine (pY) residues or surface receptors were used for detection purposes. Our observations showed that activation of Jurkat or primary human T cells using H 2 O 2 or TCR-induced stimulation led to simultaneous phosphorylation of the activating tyrosine residue, Y394 and the inhibitory tyrosine residue, Y505 of p56 lck . This was followed by downstream calcium flux and expression of T cell activation markers; CD69 and CD40 ligand (CD40L). However, the extent of measurable activation readouts depended on the optimal stimulatory conditions (temperature and/or stimuli combinations). Treatment of cells with a p56 lck -specific inhibitor, PP2, abolished phosphorylation at either residue in a dose-dependent manner. Taken together, these observations show that TCR-induced stimulation of T cells led to simultaneous phosphorylation of p56 lck residues. This implies that dephosphorylation of Y505 is not crucial for p56 lck activity. Also, it is clear that cytometric analysis provides for a rapid, sensitive, and quantitative method to supplement biochemical studies on p56 P56lck is a lymphocyte-specific member of the Src family kinases. This family of tyrosine kinases comprises of a closely related group of nonreceptor kinases which are involved in signaling pathways that control the growth and differentiation of cells in response to the activation of cell-surface receptors. Generally, Src family kinases share a common architecture that underlies a shared regulatory mechanism. The basic structure is composed of an N-terminal region, a unique region of 40-70 residues (impacting distinct localization of each member), three Src homologue (SH) domains, SH2, SH3, and SH4, the catalytic domain, and the C-terminal tail.Productive stimulation of the TCR leads to the activation of a number of signaling pathways that involve generation of second messengers, increased transcriptional activity, and production of new proteins that mediate effector functions of activated T cells. Upon receptor stimulation, the first detectable biochemical event is phosphorylation of tyrosine residues present within immunoreceptor tyrosine-based activation motifs, ITAMs. P56 lck is critical in this phosphorylation as p56 lck 2/2 mutant mice failed to devel...

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“…Analysis of T cell motility and interactions within the lymph node has established that increased T cell motility and aborted T cell interactions with APCs are associated with tolerance induction, whereas increased duration of T cell arrest and sustained interactions with APCs result in T cell activation 18,19,20,21 . Multiple mechanisms leading to this effect have been demonstrated in the pancreatic lymph nodes of NOD mice.…”

Section: Introductionmentioning

confidence: 99%

Antigen Recognition in the Islets Changes with Progression of Autoimmune Islet Infiltration

Lindsay

Corbin

Mahne

et al. 2015

The Journal of Immunology

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In type 1 diabetes, the pancreatic islets are an important site for therapeutic intervention since immune infiltration of the islets is well established at diagnosis. Therefore, understanding the events that underlie the continued progression of the autoimmune response and islet destruction is critical. Islet infiltration and destruction is an asynchronous process, making it important to analyze the disease process on a single islet basis. To understand how T cell stimulation evolves through the process of islet infiltration we analyzed the dynamics of T cell movement and interactions within individual islets of spontaneously autoimmune non-obese diabetic (NOD) mice. Using both intra-vital and explanted 2-photon islet imaging, we defined a correlation between increased islet infiltration and increased T cell motility. Early T cell arrest was antigen dependent and due, at least in part, to antigen recognition through sustained interactions with CD11c+ antigen presenting cells (APCs). As islet infiltration progressed, T cell motility became antigen-independent, with a loss of T cell arrest and sustained interactions with CD11c+ APCs. These studies suggest that the autoimmune T cell response in the islets may be temporarily dampened during the course of islet infiltration and disease progression.

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Duration of antigen receptor signaling determines T-cell tolerance or activation

Cited by 62 publications

References 22 publications

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

TCR‐induced T cell activation leads to simultaneous phosphorylation at Y505 and Y394 of p56^lck residues

Antigen Recognition in the Islets Changes with Progression of Autoimmune Islet Infiltration

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Duration of antigen receptor signaling determines T-cell tolerance or activation

Cited by 62 publications

References 22 publications

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

Differential Requirements for Th1 and Th17 Responses to a Systemic Self-Antigen

TCR‐induced T cell activation leads to simultaneous phosphorylation at Y505 and Y394 of p56lck residues

Antigen Recognition in the Islets Changes with Progression of Autoimmune Islet Infiltration

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TCR‐induced T cell activation leads to simultaneous phosphorylation at Y505 and Y394 of p56^lck residues