Selective upregulation of immune regulatory and effector cytokine synthesis by intestinal intraepithelial lymphocytes following CD43 costimulation

Montufar-Solis, Dina; Garza, Tomas; Klein, John R.

doi:10.1016/j.bbrc.2005.10.050

Cited by 12 publications

(9 citation statements)

References 35 publications

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“…As previously described for anergic cells (35), when the first activating signals were provided by the TCR, we found that cells secreted primarily IL-8. Overall, our data support reports showing that CD43 functions as a coreceptor molecule for the TCR (15,36,37) and that CD43-mediated signals up-regulate the expression of several proinflammatory genes (27,38).…”

Section: Discussionsupporting

confidence: 79%

TCR-Dependent Cell Response Is Modulated by the Timing of CD43 Engagement

Fierro

Pedraza‐Alva

Rosenstein

2006

The Journal of Immunology

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Binding of Ag by the Ag receptor in combination with other stimuli provided by costimulatory receptors triggers the expansion and differentiation of T lymphocytes. However, it is unclear whether the time when costimulatory molecules interact with their counterreceptors with regards to Ag recognition leads to different T cell responses. Provided that the coreceptor molecule CD43 is a very abundant molecule evenly distributed on the membrane of T cell surface protruding 45 nm from the cell, we hypothesized that CD43 is one of the first molecules that interacts with the APC and thus modulates TCR activation. We show that engaging CD43 before or simultaneously with the TCR inhibited Lck-Src homology 2 domain containing phosphatase-1 interaction, preventing the onset of a negative feedback loop on TCR signals, favoring high levels of IL-2, cell proliferation, and secretion of proinflammatory cytokines and chemokines. In contrast, the intracellular signals resulting of engaging the TCR before CD43 were insufficient to induce IL-2 production and cell proliferation. Interestingly, when stimulated through the TCR and CD28, cells proliferated vigorously, independent of the order with which molecules were engaged. These results indicate that CD43 induces a signaling cascade that prolongs the duration of TCR signaling and support the temporal summation model for T cell activation. In addition to the strength and duration of intracellular signals, our data underscore temporality with which certain molecules are engaged as yet another mechanism to fine tune T cell signal quality, and ultimately immune function.

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Section: Discussionsupporting

confidence: 79%

TCR-Dependent Cell Response Is Modulated by the Timing of CD43 Engagement

Fierro

Pedraza‐Alva

Rosenstein

2006

The Journal of Immunology

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“…It remains to be determined how the presence or absence of CD43 on T cells is regulating Th cell differentiation. Studies in human T cells have shown that CD43 costimulation in the presence and absence of TCR stimulation can induce IFN-␥ production and promote Th1 differentiation (42)(43)(44)(45). However, these findings have not been replicated in murine systems, making it unclear whether this plays a role in our model.…”

Section: -Immunized Cd43contrasting

confidence: 46%

CD43 Regulates Th2 Differentiation and Inflammation

Cannon

Collins

Mody

et al. 2008

The Journal of Immunology

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CD43 is a highly glycosylated transmembrane protein that regulates T cell activation. CD43−/− T cells are hyperproliferative and the cytoplasmic tail of CD43 has been found to be sufficient to reconstitute wild-type proliferation levels, suggesting an intracellular mechanism. In this study, we report that upon TCR ligation CD43−/− T cells demonstrated no increase in tyrosine phosphorylation but a decreased calcium flux. Interestingly, CD43−/− T cells preferentially differentiated into Th2 cells in vitro, and CD43−/− T cells show increased GATA-3 translocation into the nucleus. In vivo, CD43−/− mice exhibited increased inflammation in two separate models of Th2-mediated allergic airway disease. In contrast, in Th1-mediated diabetes, nonobese diabetic CD43−/− mice did not significantly differ from wild-type mice in disease onset or progression. Th1-induced experimental autoimmune encephalomyelitis to MOG35–55 was also normal in the CD43−/− mice. Nonetheless, the CD43−/− mice produced more IL-5 when restimulated with MOG35–55 in vitro and demonstrated decreased delayed-type hypersensitivity responses. Together, these data demonstrate that although CD43−/− T cells preferentially differentiate into Th2 cells, this response is not sufficient to protect against Th1-mediated autoimmune responses.

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“…Costimulatory activity of CD43 leading to enhanced proliferation has been shown through in vitro studies involving anti‐CD43 cross‐linking in conjunction with TCR–CD3 stimulation (48). More importantly, significant differences have been shown with regard to cytokine profiles elicited following CD43 costimulation compared with CD3 stimulation alone or non‐stimulated cultures (49). Of 22 analytes tested, CCL5 was the only cytokine detected in non‐stimulated cultures (49).…”

Section: Constitutively Expressed Costimulatory Moleculesmentioning

confidence: 99%

T‐cell activation in the intestinal mucosa

Montufar-Solis

Garza

Klein

2007

Immunological Reviews

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SummaryThe vast majority of peripheral T cells exist as resting lymphocytes until a signal for activation has been received. In response to antigen, this involves ligation of the T cell receptor (TCR) and signal transmission through the CD3 complex, which then initiates a cascade of intracellular events that leads to the expression of genes used in T cell activation. T cell activation also requires soluble mediators in the form of cytokines and chemokines that regulate the process in both positive and negative ways, and costimulatory signals received in conjunction with TCR/CD3 signaling are important in the activation of T cells. Unlike T cells in other peripheral immune compartments, small and large intestinal intraepithelial lymphocytes (IELs) bear some but not all properties of activated T cells, suggesting that they constitute a large population of 'partially-activated' effector cells. Because of that, regulation of the IEL activation process must be held in tight check, yet it must be ready to respond to foreign antigen rapidly and effectively. We discuss how costimulatory molecules may hold the key to controlling IEL activation through a multi-phase process beginning with cells that have already entered into the early stage of activation.

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Selective upregulation of immune regulatory and effector cytokine synthesis by intestinal intraepithelial lymphocytes following CD43 costimulation

Cited by 12 publications

References 35 publications

TCR-Dependent Cell Response Is Modulated by the Timing of CD43 Engagement

TCR-Dependent Cell Response Is Modulated by the Timing of CD43 Engagement

CD43 Regulates Th2 Differentiation and Inflammation

T‐cell activation in the intestinal mucosa

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