Inflammatory T helper 17 cells promote depression-like behavior in mice

IL-6 is sufficient to induce depressive-like behavior in rodent models.

“is sufficient to induce depressive-like behavior in rodent models”

• cites [3] Dantzer, 2008, From inflammation to sickness and depression: When the immune system subjugates the brain, Nat Rev Neurosci sourceDisputed

  The passage on cytokine-induced behaviour (labelled Abstract in our copy) says that IL-6 administered systemically or centrally has no behavioural effect, despite inducing fever. It therefore contradicts the claim that IL-6 alone is sufficient to induce depressive-like behaviour in rodents. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [4] Miller, 2009, Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression, Biol Psychiatry sourcePartly supported

  The ‘Evidence for a Cytokine Basis for Major Depression’ section says cytokines and cytokine inducers can produce depression-like behavioral changes in laboratory animals. It does not say that IL-6 alone is sufficient to induce those changes in rodents; the passages mentioning IL-6 concern associations in humans, not that experiment. Page numbers are unavailable in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [5] Chourbaji, 2006, IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors, Neurobiol Dis sourceNot checked — no full text of the source
• cites [8] Monje, 2011, Constant darkness induces IL-6-dependent depression-like behavior through the NF-kappaB signaling pathway, J Neurosci sourceSupported

IL-6 is elevated in the serum of a subset of depressed patients.

“the inflammatory cytokine interleukin-6 (IL-6) is elevated in the serum of a subset of depressed patients”

• cites [3] Dantzer, 2008, From inflammation to sickness and depression: When the immune system subjugates the brain, Nat Rev Neurosci sourcePartly supported

  The discussion of cytokines in depression (labelled Abstract in our copy; page unavailable) says patients with severe clinical depression have increased blood concentrations of inflammatory biomarkers, while noting these markers are not always elevated. It does not identify IL-6 as the elevated serum marker, so the IL-6-specific part of the claim is unsupported. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [4] Miller, 2009, Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression, Biol Psychiatry sourceSupported
• cites [5] Chourbaji, 2006, IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors, Neurobiol Dis sourceNot checked — no full text of the source
• cites [8] Monje, 2011, Constant darkness induces IL-6-dependent depression-like behavior through the NF-kappaB signaling pathway, J Neurosci sourcePartly supported

  The Introduction (page unavailable) says IL-6 is frequently elevated in depressed patients, and the discussion describes it as a peripheral biomarker of depression. Those passages support the general claim, but they do not specify serum; the paper discusses circulating IL-6 and cites a finding about plasma concentrations instead. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Inflammatory cytokines that direct T cell subtype production are altered in depressed patients.

“Since inflammatory cytokines that direct T cell subtype production are altered in depressed patients (12–14)”

• cites [12] Cope, 1997, Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling, J Exp Med sourcePartly supported

  The Results section, “Prolonged TNF Exposure In Vitro Suppresses Th1 and Th2 Cell Subsets” (page unavailable), reports that TNF alters cytokine production and suppresses both Th1- and Th2-like T-cell responses. These findings concern mouse T cells, not depressed patients; our copy does not establish that the cytokines are altered in that population. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [13] Lee, 2008, Genomic expression profiling of TNF-alpha-treated BDC2.5 diabetogenic CD4+ T cells, Proc Natl Acad Sci U S A sourceCould not verify

  The paper’s Discussion describes how TNF exposure affects T-cell signaling, and its mouse-study summary reports changes in genes involved in cytokine synthesis. Neither passage addresses cytokine levels in depressed patients or cytokines directing T-cell subtype production. Searches for depression, depressed patients, and T-cell differentiation found no passage supporting those points. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [14] Cope, 1994, Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis, J Clin Invest sourcePartly supported

  The Results (p. 754) report altered T-cell cytokine production after TNF treatment in culture. The Introduction discusses abnormal cytokine responses in rheumatoid arthritis, not depression. Our copy does not establish that cytokines directing T-cell subtype production are altered in depressed patients. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Deletion of the IL-6 gene is protective against depressive-like behavior in rodent models.

“whereas deletion of the IL-6 gene is protective (3–5, 8)”

• cites [3] Dantzer, 2008, From inflammation to sickness and depression: When the immune system subjugates the brain, Nat Rev Neurosci sourcePartly supported

  The passage on IL-6-deficient mice (section labelled Abstract; page unavailable) reports reduced LPS-induced sickness behaviour and cognitive impairment, not reduced depressive-like behaviour. The paper distinguishes sickness behaviour from depressive-like behaviour, so it does not establish the claimed protection against the latter. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [4] Miller, 2009, Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression, Biol Psychiatry sourceCould not verify

  The Cytokine Effects on Neural Plasticity section reports protection from stress-related behavioral effects with IL-1 receptor knockout mice, not IL-6 gene deletion. Searches for IL-6 knockout mice, IL-6 gene deletion, and protection from depressive-like behavior found no passage in our copy addressing the claimed result; page numbers were unavailable. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [5] Chourbaji, 2006, IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors, Neurobiol Dis sourceNot checked — no full text of the source
• cites [8] Monje, 2011, Constant darkness induces IL-6-dependent depression-like behavior through the NF-kappaB signaling pathway, J Neurosci sourceSupported

IL-6 drives the production of Th17 cells.

“IL-6, which drives the production of T helper 17 (Th17) cells”

• cites [9] Butovsky, 2006, Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells, Mol Cell Neurosci sourceNot checked — no full text of the source
• cites [10] Kebir, 2007, Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation, Nat Med sourceCould not verify

  The passage labeled Abstract reports that the authors generated human Th17 cells by culturing CD4+ lymphocytes with IL-23, but it does not address whether IL-6 drives Th17-cell production. Another passage says IL-17 induced IL-6 expression in blood-brain barrier endothelial cells—the reverse of the relationship claimed. Searches for IL-6 and Th17 differentiation found no passage establishing the claim; the IL-23 method does not rule it out. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [11] Komiyama, 2006, IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis, J Immunol sourceCould not verify

  The section on CD4+ T cells during EAE identifies those cells as the main IL-17 producers, but does not discuss IL-6 driving Th17-cell production. A search for IL-6 and Th17 differentiation found no passage addressing that relationship; the paper instead reports that IL-23 promoted IL-17 production. Page numbers were not available in our copy. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

Maintenance of certain brain functions is dependent on T cell actions in the CNS.

“maintenance of certain brain functions is dependent on T cell actions in the CNS (31, 32)”

• cites [31] Ransohoff, 2012, Innate immunity in the central nervous system, J Clin Invest sourceCould not verify

  The section “Interactions between innate immune cells and T cells in the CNS” discusses T-cell-mediated inflammation, host defense, and repair after injury, but does not say that maintaining brain functions depends on T-cell actions. Searches for normal brain function, cognition, learning, and neural repair found no passage establishing that dependency. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [32] Schwartz, 2010, Systemic inflammatory cells fight off neurodegenerative disease, Nat Rev Neurol sourceNot checked — no full text of the source

Heterozygote Rorc(γT)+/GFP mice produce a greatly diminished Th17 cell population because of the reduction of RORγT expression.

“heterozygote Rorc(γT)+/GFP mice, which produce a greatly diminished Th17 cell population because of the reduction of RORγT expression (48), as we recently confirmed (37)”

• cites [48] Ivanov, 2006, The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells, Cell sourceNot checked — no full text of the source
• cites [37] Beurel, 2011, Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells, J Immunol sourceSupported

Th17 cells are deleterious to the CNS.

“Th17 cells are deleterious to the CNS”

• cites [9] Butovsky, 2006, Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells, Mol Cell Neurosci sourceNot checked — no full text of the source
• cites [10] Kebir, 2007, Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation, Nat Med sourceSupported
• cites [11] Komiyama, 2006, IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis, J Immunol sourcePartly supported

  The Abstract and the section on EAE induction by CD4 T cells (page not available in our copy) show that IL-17-producing CD4 T cells promote a mouse disease marked by CNS inflammation and demyelination. That supports a deleterious role in this EAE model, but the unqualified claim extends beyond the condition the paper studied. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [24] Ziv, 2006, Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood, Nat Neurosci sourceNot checked — no full text of the source

Exposure to only escapable foot shocks, without a prior session of inescapable foot shocks, causes learned helplessness behavior in a portion of GSK3 knockin mice, but not wild-type mice.

“Exposure to only escapable foot shocks, without a prior session of inescapable foot shocks, causes learned helplessness behavior in a portion of GSK3 knockin mice, but not wild-type mice (34).”

• cites [34] Polter, 2010, Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances, Neuropsychopharmacology sourceSupported

Immune system actions profoundly impact mood regulation.

“a growing recognition that immune system actions profoundly impact mood regulation (3–6)”

• cites [3] Dantzer, 2008, From inflammation to sickness and depression: When the immune system subjugates the brain, Nat Rev Neurosci sourceSupported
• cites [4] Miller, 2009, Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression, Biol Psychiatry sourceSupported
• cites [5] Chourbaji, 2006, IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors, Neurobiol Dis sourceNot checked — no full text of the source
• cites [6] Licinio, 1999, The role of inflammatory mediators in the biology of major depression: Central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection, Mol Psychiatry sourceNot checked — no full text of the source

Targets of inflammatory molecules contribute to establishing a pro-depressant environment.

“The growing evidence of causative links between inflammation and depression (3, 4) indicates that targets of inflammatory molecules contribute to establishing a pro-depressant environment.”

• cites [3] Dantzer, 2008, From inflammation to sickness and depression: When the immune system subjugates the brain, Nat Rev Neurosci sourceSupported
• cites [4] Miller, 2009, Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression, Biol Psychiatry sourceSupported

Increases in Th17 and Th1 cells may be linked to evidence that Th1 cells can be derived from Th17 cells.

“these associated increases in Th17 and Th1 cells may be linked to recent evidence that Th1 cells can be derived from Th17 cells (51).”

• cites [51] Hirota, 2011, Fate mapping of IL-17-producing T cells in inflammatory responses, Nat Immunol sourceSupported

The effect of lithium may be due to the previously identified action of GSK3 inhibitors to block Th17 cell production.

“which may be due to the previously identified action of GSK3 inhibitors to block Th17 cell production (37).”

• cites [37] Beurel, 2011, Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells, J Immunol sourceSupported

Th17-recipient mice did not differ from vehicle-treated controls in locomotor activity in a novel open field.

“Th17-recipient mice did not differ from vehicle-treated controls in locomotor activity in a novel open field (Supplemental Figure S2A)”

Chronic restraint stress resulted in increased brain levels of Th1 cells.

“chronic restraint stress resulted in increased brain levels of Th17 cells (Figure 1E) and Th1 cells (Figure 1F).”

Rorc(γT)+/GFP mice had lower total CD4+ T cells in the brain compared with wild-type mice.

“lower total CD4+ T cells (Figure 3D)”

Lithium pretreatment blocked the increases in brain Th17 and Th1 cells.

“and blocked the increases in brain Th17 and Th1 cells”

Th17-recipient mice did not exhibit overt changes in sociability as estimated by time spent in the chamber with a novel conspecific mouse.

“Although Th17-recipient mice did not exhibit overt changes in sociability as estimated by time spent in the chamber with a novel conspecific mouse”

The numbers of Th17 cells, but not Th1 cells or Tregs, were greater in the spleens of learned helpless mice than in nonlearned helpless mice or in mice treated with lithium.

“The numbers of Th17, but not Th1 cells or Tregs, also were greater in the spleens of learned helpless mice than in nonlearned helpless mice or in mice treated with lithium (Figure 1D).”

There was no difference in weight loss between Th17-recipient and control groups.

“there was no difference in weight loss between groups (Supplemental Figure S3B)”

Mouse brain Th17 cells were increased by chronic restraint stress.

“chronic restraint stress resulted in increased brain levels of Th17 cells (Figure 1E)”

The spleens of Th17 recipient mice contained elevated levels of IL-17A+ CD4+ T cells.

“The spleens of Th17 recipient mice also contained elevated levels of IL-17A+ CD4+ T cells”

Mouse brain Th17 cells were increased by learned helplessness.

“The number of Th17 cells, which are identified by positive co-staining for CD4+ and for IL-17A (i.e., IL-17A+ CD4+ T cells) was increased by 78% in the learned helplessness mouse brains compared to the non-depressed mice”

Rorc(γT)+/GFP mice did not differ from littermate wild-type mice in locomotor activity in a novel open field.

“Rorc(γT)+/GFP mice did not differ from littermate wild-type mice in locomotor activity in a novel open field (Figure 3A).”

There was no difference in brain T regulatory cells between learned helpless and non-depressed mice.

“whereas there was no difference between groups in T regulatory cells (Tregs; FoxP3+ CD4+ T cells) (Figure 1B)”

RORγT knockout mice exhibited strong resistance to learned helplessness.

“RORγT knockout mice exhibited strong resistance to learned helplessness (Supplemental Figure S4A)”

89% of Th17-recipient mice met the learned helplessness criteria of >15 failures out of 30 trials after reduced-intensity inescapable foot shocks that did not induce learned helplessness in vehicle- or undifferentiated CD4+ T cell-treated control mice.

“Mice were subjected to inescapable foot shocks of reduced intensity that did not induce learned helplessness in vehicle- or undifferentiated CD4+ T cell-treated control mice, whereas 89% of Th17-recipient mice met the learned helplessness criteria of >15 failures out of 30 trials (Figure 2A).”

The spleens of Th17 recipient mice showed a slight but statistically significant increase in total CD4+ T cells.

“and a slight but statistically significant increase in total CD4+ T cells”

Th17-recipient mice had reduced nose contacts indicating diminished social interaction.

“reduced nose contacts indicated diminished social interaction (Figure 2E)”

Rorc(γT)+/GFP mice displayed a robust 3-fold increase in resistance to acquisition of learned helplessness compared with wild-type mice, with 75% of Rorc(γT)+/GFP mice resistant versus 25% of wild-type mice.

“Although in these mice Th17 cells were only partially depleted, not abolished, the mice nevertheless displayed a robust 3-fold increase in resistance to acquisition of learned helplessness, with 75% of the Rorc(γT)+/GFP mice resistant to a paradigm in which only 25% of wild-type mice were resistant.”

The numbers of Th17 and Th1 cells were significantly higher in the brains of GSK3 knockin mice that failed to escape than in those that escaped.

“the numbers of Th17 and Th1 cells were significantly higher in the brains of GSK3 knockin mice that failed to escape than in those that escaped”

Treatment with anti-IL-17A antibodies reduced Th17-dependent learned helplessness.

“Treatment with the RORγT inhibitor SR1001, or anti-IL-17A antibodies to abrogate Th17 cell function, reduced Th17-dependent learned helplessness.”

Treatment with the RORγT inhibitor SR1001 reduced Th17-dependent learned helplessness.

“Treatment with the RORγT inhibitor SR1001, or anti-IL-17A antibodies to abrogate Th17 cell function, reduced Th17-dependent learned helplessness.”

Wild-type mice maintained learned helpless behavior throughout the test in contrast to Rorc(γT)+/GFP mice.

“The latency time to escape also demonstrated that the wild-type mice maintained learned helpless behavior throughout the test in contrast to the Rorc(γT)+/GFP mice (Figure 3C).”

The spleens of Th17 recipient mice showed no changes of other cell types.

“but no changes of other cell types (Supplemental Figure 3)”

Th17-recipient mice contained elevated brain levels of IL-17A+ CD4+ T cells (Th17 cells).

“The Th17-recipient mice contained elevated brain levels of IL-17A+ CD4+ T cells (Th17 cells)”

Rorc(γT)+/GFP mice had lower levels of IL-17A+ CD4+ T cells (Th17 cells) in the brain after the learned helplessness paradigm compared with wild-type mice.

“Evaluation of cells in the brains of mice after the learned helplessness paradigm confirmed that, compared with wild-type mice, Rorc(γT)+/GFP mice had lower levels of IL-17A+ CD4+ T cells (Th17 cells)”

A single session of only escapable foot shocks induced learned helplessness in ~40% of GSK3 knockin mice.

“A single session of only escapable foot shocks induced learned helplessness in ~40% of GSK3 knockin mice (Figure 1G).”

Brain Th1 cells were increased by 27% in learned helpless mice compared to non-depressed mice.

“A 27% increase in brain Th1 cells, which are identified by positive co-staining for CD4+ and IFNγ (IFNγ+ CD4+ T cells), was found in learned helpless mice”

Rorc(γT)+/GFP mice had no difference in FoxP3+ CD4+ T cells (Tregs) in the brain compared with wild-type mice.

“no difference in FoxP3+ CD4+ T cells (Tregs)”

In the NSF test, Th17-recipient mice displayed significantly longer latencies to feed when placed in a novel arena with food following 24 hr food deprivation compared with control CD4+ T cell-treated mice.

“In the NSF test, Th17-recipient mice displayed significantly longer latencies to feed when placed in a novel arena with food following 24 hr food deprivation compared with control CD4+ T cell-treated mice (Figure 2D).”

Th17-recipient mice did not differ from vehicle-treated controls in pain sensitivity.

“or pain sensitivity (Supplemental Figure S2B).”

The numbers of macrophages and DCs were the same in GSK3 knockin mice that failed to escape and those that escaped.

“while the numbers of macrophages and DCs were the same in both groups (Figure 1H)”

Chronic restraint stress resulted in a 15% lowered body weight.

“substantiated by a 15% lowered body weight (Supplemental Figure S1), a marker of chronic stress.”

Lithium pretreatment reduced the percent of mice meeting learned helplessness criteria from 60% to 10%.

“Lithium pretreatment reduced the percent of mice meeting learned helplessness criteria from 60% to 10%”

SR1001 treatment significantly reduced Th17 cells in the spleen and brain.

“Measurements of Th17 cells in the spleen and brain demonstrated a significant reduction of Th17 cells after SR1001 treatment (Supplemental Figure S5).”

Th17 cells accumulate in the brains of mice subjected to two models of depression-like behavior.

“We found that Th17 cells accumulate in the brains of mice subjected to two models of depression-like behavior”

Reducing Th17 cells provided resistance to learned helplessness.

“reducing Th17 cells provided resistance to learned helplessness.”

A 78% increase of Th17 cells was found in the brains of mice that displayed learned helplessness.

“including a 78% increase of Th17 cells in the brains of mice that displayed learned helplessness.”

Anti-inflammatory Treg levels were not altered in these conditions.

“In contrast, anti-inflammatory Treg levels were not altered in these conditions”

Administration of Th17 cells promoted three behavioral models of depression.

“administration of Th17 cells promoted three behavioral models of depression”

89% of mice developed learned helplessness after receiving Th17 cells two days previously.

“Remarkably, 89% of mice developed learned helplessness after receiving Th17 cells two days previously”

Significant immune alterations were found in RORγT knockout mice.

“Indeed, we found significant immune alterations in RORγT knockout mice”

F4/80+CD45high cells (activated macrophages) and CD11c+CD45high cells (DCs) were lower in Rorc(γT)+/GFP mice than wild-type mice.

“F4/80+CD45high cells (activated macrophages) and CD11c+CD45high cells (DCs) were lower in Rorc(γT)+/GFP mice than wild-type mice (Figure 3E).”

Depression is likely associated with changes in T cell subtypes.

“it is likely that depression is associated with changes in T cell subtypes.”

T cells directly impact the brain.

“T cells have been shown to directly impact the brain.”

There is some evidence that mood-related behaviors in rodents are influenced by T cells.

“there is some evidence that mood-related behaviors in rodents are influenced by T cells (19–22)”

• cites [19] Cohen, 2006, Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells, J Neurobiol sourceNot checked — no full text of the source
• cites [20] Lewitus, 2008, Reducing post-traumatic anxiety by immunization, Brain Behav Immun sourceNot checked — no full text of the source
• cites [21] Hickie, 1993, Impaired in vivo immune responses in patients with melancholia, Br J Psychiatry sourceNot checked — no full text of the source
• cites [22] Pariante, 2001, Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment, Biol Psychiatry sourceNot checked — no full text of the source

Depression is associated with an environment capable of altering the population of subsets of CD4+ T cells.

“depression is associated with an environment capable of altering the population of subsets of CD4+ T cells”

Antidepressant effects may be attained by targeting Th17 cells.

“suggesting antidepressant effects may be attained by targeting Th17 cells.”

There was no difference in blood brain barrier permeability between mice that were or were not learned helpless.

“indicating there was no difference in blood brain barrier permeability between mice that were or were not learned helpless, which would be evident by an increase in the number of infiltrated DCs and macrophages.”

Elevation of Th17 cells is sufficient to increase susceptibility to the learned helplessness model of depression-like behavior.

“These results demonstrate that elevation of Th17 cells is sufficient to increase susceptibility to the learned helplessness model of depression-like behavior.”

RORγT is a transcription factor that drives the differentiation of Th17 cells.

“a transcription factor that drives the differentiation of Th17 cells that is thought to be expressed almost exclusively in Th17 cells (48)”

• cites [48] Ivanov, 2006, The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells, Cell sourceNot checked — no full text of the source

Th17 cells promote depression-like behaviors in mice.

“promote depression-like behaviors in mice”

RORγT knockout mice have multiple alterations in their immune system.

“examination of the immune system of these mice revealed multiple alterations (48)”

• cites [48] Ivanov, 2006, The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells, Cell sourceNot checked — no full text of the source

Th17 cells are absent in mice with depleted RORγT.

“Th17 cells are absent in mice with depleted retinoid-related orphan receptor-γT (RORγT)”

• cites [48] Ivanov, 2006, The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells, Cell sourceNot checked — no full text of the source

The resistance of RORγT knockout mice to learned helplessness is consistent with the postulate that Th17 cells promote this behavior.

“consistent with the postulate that Th17 cells promote this behavior.”

Specifically inhibiting the production or function of Th17 cells reduces vulnerability to depression-like behavior.

“specifically inhibiting the production or function of Th17 cells reduces vulnerability to depression-like behavior”

Administration of Th17 cells was sufficient to impair several behaviors that have been associated with depression.

“Thus, administration of Th17 cells was sufficient to impair several behaviors that have been associated with depression.”

Modulation of RORγT is a potential intervention.

“identifying modulation of RORγT as a potential intervention.”

Conditions causing depression-like behavior consistently increased mouse brain Th17 and Th1 cells.

“Thus, conditions causing depression-like behavior consistently increased mouse brain Th17 and Th1 cells.”

Th17 cells are increased in the brain during depression-like states.

“These findings indicate that Th17 cells are increased in the brain during depression-like states”

The adaptive immune system, in particular the Th17 cell burden, profoundly affects stress-induced behavioral responses that may model mood dysregulation.

“Thus, the adaptive immune system, in particular the Th17 cell burden, profoundly affects stress-induced behavioral responses that may model mood dysregulation.”

Pharmacological intervention aimed at Th17 cell production provides resistance to Th17 cell-dependent depressive-like behavior.

“Moreover, inhibition of RORγT confirmed that pharmacological intervention aimed at Th17 cell production provides resistance to Th17 cell-dependent depressive-like behavior”

Th17 cells may contribute to the development of depression-like behavior.

“raising the possibility that Th17 cells may contribute to the development of depression-like behavior.”

• AssumptionRests on an assumption: In the learned helplessness paradigm, all mice received the same aversive stimuli, which is well-established to produce learned helplessness in only a portion of treated mice.

Brain Th17 cells increase with depressive-like behavior.

“Thus, brain Th17 cells increase with depressive-like behavior”

Blocking Th17 actions provides antidepressant effects in Th17-dependent learned helplessness.

“These findings confirmed that blocking Th17 actions provide antidepressant effects in Th17-dependent learned helplessness.”

The adaptive immune system significantly impacts susceptibility to learned helplessness and other behaviors that may be relevant to mood regulation.

“These findings demonstrate that the adaptive immune system significantly impacts susceptibility to learned helplessness and other behaviors that may be relevant to mood regulation”

Th17 cells significantly contribute to promote susceptibility to depressive-like behavior.

“These findings indicate for the first time a significant contribution of Th17 cells to promote susceptibility to depressive-like behavior.”

IL-17A is a critical cytokine mediating Th17-dependent learned helplessness.

“The antidepressant effect of anti-IL-17A therapy demonstrated that IL-17A is a critical cytokine mediating Th17-dependent learned helplessness”

Reduction of Th17 cells increases resistance to learned helplessness behavior.

“Thus, Rorc(γT)+/GFP mice displayed a remarkable resistance to learned helplessness behavior in this paradigm that is robustly effective in wild-type mice, further indicating that reduction of Th17 cells increases resistance to learned helplessness behavior.”

Proinflammatory cytokines are driving the pathogenic T cells.

“suggesting that proinflammatory cytokines are driving the pathogenic T cells.”

Even partial reduction of Th17 cell production provides significant protection from the vulnerability of mice to learned helplessness.

“Thus, even partial reduction of Th17 cell production provides significant protection from the vulnerability of mice to learned helplessness.”

Intervening at the level of IL-17A or RORγT is sufficient to neutralize the Th17-dependent depression-like behavior effect.

“and intervening at the level of IL-17A or RORγT is sufficient to neutralize the Th17-dependent depression-like behavior effect.”

Methods capable of reducing Th17 cell levels in vivo are limited.

“Methods capable of reducing Th17 cell levels in vivo are limited, with RORγT knockout mice being the most widely used approach (48, 49).”

• cites [48] Ivanov, 2006, The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells, Cell sourceNot checked — no full text of the source
• cites [49] Huang, 2007, Retinoid-related orphan receptor gamma t is a potential therapeutic target for controlling inflammatory autoimmunity, Expert Opin Ther Targets sourceNot checked — no full text of the source

Th17 cells have a causative role in depression-like behaviors.

“A causative role for Th17 cells in depression-like behaviors is supported by the findings that altering Th17 cells in mice modified the behavioral outcomes.”