Cutting Edge: CD4 T Cell-Mast Cell Interactions Alter IgE Receptor Expression and Signaling

Kashyap, Mohit; Thornton, Angela M.; Norton, Sarah K.; Barnstein, Brian; Macey, Matthew; Brenzovich, Jennifer; Shevach, Ethan M.; Leonard, Warren J.; Ryan, John

doi:10.4049/jimmunol.180.4.2039

Cited by 80 publications

(71 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since Treg normally suppress inflammation, one cannot rule out the possibility that depletion of Treg will escalate inflammation and accelerate progression of CRC. MC are known to recruit Treg (35), to mediate Treg suppression of host-vs-graft rejection responses (7), and we have now demonstrated that they can also render the Treg proinflammatory. We predict that a safer therapeutic strategy in CRC may be to target the Treg and MC interaction to hinder the generation of ΔTreg.…”

Section: Mc-mediated Diversion Of Treg To Proinflammatory Phenotype Doesmentioning

confidence: 93%

In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction

Blatner

Bonertz

Beckhove

et al. 2010

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

129

128

View full text Add to dashboard Cite

T-regulatory cells (Treg) and mast cells (MC) are abundant in colorectal cancer (CRC) tumors. Interaction between the two is known to promote immune suppression or loss of Treg functions and autoimmunity. Here, we demonstrate that in both human CRC and murine polyposis the outcome of this interaction is the generation of potently immune suppressive but proinflammatory Treg (ΔTreg). These Treg shut down IL10, gain potential to express IL17, and switch from suppressing to promoting MC expansion and degranulation. This change is also brought about by direct coculture of MC and Treg, or culture of Treg in medium containing IL6 and IL2. IL6 deficiency in the bone marrow of mice susceptible to polyposis eliminated IL17 production by the polyp infiltrating Treg, but did not significantly affect the growth of polyps or the generation of proinflammatory Treg. IL6-deficient MC could generate proinflammatory Treg. Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell–suppressive properties. IL6 and IL17 are not needed in this process.

show abstract

Section: Mc-mediated Diversion Of Treg To Proinflammatory Phenotype Doesmentioning

confidence: 93%

In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction

Blatner

Bonertz

Beckhove

et al. 2010

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

129

128

View full text Add to dashboard Cite

show abstract

“…On the same line, some of us have recently found that histamine might protect from EAE because mice unable to synthesize histamine because of a genetic deficit in the histidine decarboxylase develop exacerbated disease on MOG immunization. 33 A recent report shows Tregs inhibiting Fc⑀RI expression in MC, 34 a process that may result in the impairment of certain MC functions and, as a consequence, in altered T-cell activation. However, we could not find any difference in Fc⑀RI expression on MC, in coculture with or without Tregs (not shown), or in Treg-depleted or replete animals in vivo.…”

Section: Discussionmentioning

confidence: 99%

Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation

Piconese

Gri

Tripodo

et al. 2009

Blood

193

177

View full text Add to dashboard Cite

IntroductionTraditionally associated with the allergic response, mast cells (MCs) are now viewed as important players in a variety of immune processes, such as pathogen clearance, graft acceptance, tumor immunity, and many inflammatory and autoimmune diseases, where they exhibit either pro-or anti-inflammatory potential depending on the context. 1 Interactions of MCs with T cells have a functional role in some T cell-mediated pathologies, such as neutrophilic airway inflammation, 2,3 and autoimmune disease of the central nervous system (CNS). 4 MC-deficient mouse models show reduced development of both allergic and neutrophilic airway hyperreactivity (AHR). 2,3 MCderived tumor necrosis factor-␣ (TNF-␣) is required for T helper cell (Th17) development in the lung on ovalbumin (OVA) challenge of OTII transgenic mice, 3 a neutrophilic AHR model strictly dependent on interleukin-17 (IL-17). 5 In multiple sclerosis, MCs colocalize with demyelinating plaques in inflamed brain, and many MC-associated markers have been detected in the affected tissue. 6 The MC-deficient strain Kit W/W-v shows decreased incidence and severity of experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis. 7 MCs could be directly activated during EAE by either the specific myelin peptides or locally released agonists, including complement, cytokines, and neuropeptides, but also indirectly stimulated via Fc⑀RI by specific IgE elicited on activation of Th2 response. 1,8 In the CNS, the local release of inflammatory cytokines, proteases, oxygen radicals, and chemokines by MCs directly contributes to myelin degradation, disruption of the blood-brain barrier, and recruitment and activation of other immune cells as T lymphocytes and granulocytes in the brain parenchyma, thus exacerbating the effector phase of autoimmune response. 4 MCs are also thought to be involved in initiating EAE, through the interaction with dendritic cells and T cells in secondary lymphoid organs. 9 IL-17-secreting Th17 are considered one of the major pathogenic immune components in both EAE 10 and neutrophilic AHR. 3 Th17 cells differentiate from uncommitted precursors on antigenic activation and costimulation in the concomitant presence of a suppressive and a pro-inflammatory signal delivered by transforming growth factor-␤ (TGF-␤) and IL-6 and/or IL-21, respectively. Once primed in lymph nodes, pathogenic Th17 cells reach the inflamed tissue where they recruit granulocytes and intensify inflammation. 11 Regulatory T cells (Tregs) are one of the most relevant sources of TGF-␤ both in vitro and in vivo. This CD4 ϩ T lymphocyte subset, characterized by the constitutive expression of several costimulatory molecules and the transcription factor Foxp3, is endowed with immune-suppressive properties necessary to induce and maintain tolerance. 12 Recent findings support the notion of Treg plasticity in vivo because inflammatory stimuli can counteract Treg suppression and even promote differentiation into pathogenic Th17 cells. 13 MCs may directly or...

show abstract

“…15 Tregs have been shown to broadly suppress activation, proliferation, and/or effector functions of various immune cell populations such as conventional CD4 ϩ and CD8 ϩ T cells, 16 natural killer (NK) T cells, 17 B cells, 18 dendritic cells, 19 monocytes/macrophages, 20 neutrophils, 21 and mast cells. 22 Depletion of CD4 ϩ CD25 ϩ T cells induces effective antitumor immunity, enhances immune responses to invading microbes, triggers allergic responses to innocuous environmental substances, and breaks fetus-maternal tolerance during pregnancy. 11 On the other hand, Tregs have been found to suppress several T cellmediated immune pathologies, including allergic responses and autoimmune diseases such as type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), gastritis, colitis, glomerulonephritis, and polyarthritis as well as allograft rejection and graft-versus-host disease (GVHD).…”

Section: Introductionmentioning

confidence: 99%

Phosphoantigen-activated Vγ2Vδ2 T cells antagonize IL-2–induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection

Gong

Shao

Wang

et al. 2009

Blood

View full text Add to dashboard Cite

IntroductionHuman ␥␦ T cells appear to belong to nonclassical T cells that contribute to both innate and adaptive immune responses. Circulating V␥2V␦2 (also termed V␥9V␦2) T cells exist only in primates and, in humans, constitute 60% to 95% of total blood ␥␦ T cells. V␥2V␦2 T cells in primates can be activated by nonpeptidic phosphorylated metabolites of isoprenoid biosynthesis (eg, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate [HMBPP], isopentenyl pyrophosphate [IPP], and its isomer dimethylallyl pyrophosphate [DMAPP]). [1][2][3] We have recently shown that HMBPP is associated with antigen-presenting cell (APC) membrane and specifically recognized by V␥2V␦2 T-cell receptor (TCR) expressed on V␥2V␦2 T cells. 4 Although HMBPP produced by mycobacteria/other microbes is a potent activator for V␥2V␦2 T cells, these ␥␦ T cells possess both innate and adaptive immune features. [5][6][7][8] The finding that "unprimed" V␥2V␦2 T cells can recognize and react to wide ranges of nonpeptide phospholigands with the capability of "naive" production of cytokines has been interpreted as a pattern recognition-like feature of innate immune cells. On the other hand, the capacity of V␥2V␦2 T cells to undergo major clonal expansion in primary infection and to mount rapid recall-like expansion upon reinfection has been proposed as adaptive immune response of these ␥␦ T cells. 8 Consistent with these memory-type responses is the demonstration of memory phenotypes of V␥2V␦2 T cells in the blood of humans. 9 Accumulating evidence suggests that V␥2V␦2 T cells play a role in mediating immunity against microbial pathogens 8 and tumors. 10 Foxp3-expressiong CD4 ϩ CD25 ϩ regulatory T cells (Tregs) control immune responses to self-antigens and foreign antigens and play a major role in maintaining the balance between immunity and tolerance. 11-14 Murine CD4 ϩ CD25 ϩ regulatory T cells are induced by transforming growth factor ␤ (TGF-␤), although TGF-␤ plus IL-6 favors the development of Th17 cells. 15 [23][24][25][26] We and others have also shown that IL-2 plus phospholigand treatment can induce remarkable expansion of V␥2V␦2 T cells in nonhuman primates. 1,27,28 We therefore took advantage of the IL-2-based in vivo model systems to assess potential interplay or mutual regulation between V␥2V␦2 T cells and Tregs during early mycobacterial infection in nonhuman primates. We found that phosphoantigenactivated V␥2V␦2 T cells were able to down-regulate IL-2-induced expansion of Tregs, and antagonize Treg-driven suppression of in vivo immune responses. Methods AnimalsFour-to 8-year-old, 3-to 4-kg cynomolgus macaques (Macaca fascicularis) were used in this study. A total of 18 monkeys were divided into 3 groups, 6 for each. All animals were maintained and used in accordance with the guidelines of the institutional animal care and use committee of all participating institutions. Animals were anesthetized with 10 mg/kg ketamine HCl (Fort Dodge Animal Health, Fort Dodge, IA) intramuscularly for all blood sampling and treatments. EDTA-anticoagulated...

show abstract

Cutting Edge: CD4 T Cell-Mast Cell Interactions Alter IgE Receptor Expression and Signaling

Cited by 80 publications

References 33 publications

In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction

In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction

Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation

Phosphoantigen-activated Vγ2Vδ2 T cells antagonize IL-2–induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection

Contact Info

Product

Resources

About