Distinct characteristics of hippocampal pathogenic th17 cells in a mouse model of depression

Donor CD45.1+CD4+ cells were found in the hippocampi after learned-helplessness.

“Donor CD45.1+CD4+ cells were found in the hippocampi after learned-helplessness even though, being undifferentiated, they are not sufficient to promote learned-helplessness (Beurel et al., 2013) (Fig 2C).”

• cites Beurel et al., 2013 sourcePartly supported

  The Results (page unavailable) report CD4+ T cells in mouse brains after the learned-helplessness paradigm, and the Methods describe transferring CD4+ T cells. The Results also say undifferentiated CD4+ T cell-treated controls did not develop learned helplessness under the reduced-intensity protocol. Our copy does not identify the brain cells as CD45.1+ donor cells or locate them specifically in the hippocampi. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

The reduced intensity paradigm did not induce learned-helplessness in most wild-type mice.

“that did not induce learned-helplessness in most wild-type mice (Beurel et al., 2013).”

• cites Beurel et al., 2013 sourceSupported

IL-17A is elevated in some but not all depressed patients.

“IL-17A was elevated in some (Chen et al., 2011; Davami et al., 2016), but not all (Kim et al., 2013; Liu et al., 2012), depressed patients”

• cites Chen et al., 2011 sourceNot checked — no full text of the source
• cites Davami et al., 2016 sourceSupported
• cites Kim et al., 2013 sourceSupported

TH17 cells accumulate in the brains of mice that exhibit depressive-like behaviors.

“We previously reported that T helper (TH) CD4+ cells expressing IL-17A (TH17) cells promote susceptibility to depressive-like behaviors in non-lymphopenic mice and accumulate in the brains of mice that exhibit depressive-like behaviors (Beurel et al., 2013).”

• cites Beurel et al., 2013 sourceSupported

Reduced levels of CCR6 expression were found in the blood of MDD patients.

“However, reduced levels of CCR6 expression were found in the blood of MDD patients, suggesting that cells expressing CCR6 might already have reached the brain or other organs (Patas et al., 2018; Powell et al., 2014).”

• cites Patas et al., 2018 sourceSupported
• cites Powell et al., 2014 sourceSupported

TH17 cells accumulate in the brains of learned-helpless mice.

“TH17 cells accumulate in the brains of learned-helpless mice (Beurel et al., 2013).”

• cites Beurel et al., 2013 sourceSupported

PD-1 is known to induce anergy in TH17 cells.

“This reveals a potential mechanism whereby CCR6 controls pathogenicity of TH17 cells in learned-helplessness because PD-1 is known to induce anergy in TH17 cells (Luz-Crawford et al., 2012).”

• cites Luz-Crawford et al., 2012 sourcePartly supported

  The Discussion says PD-L1 signaling through PD-1 can induce anergy in T cells generally. The Results show that this pathway helps suppress mature Th17-cell proliferation and function, but do not establish that it induces anergy specifically in Th17 cells. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Adoptively transferred TH17 cells induce endogenous TH17 cell differentiation in wild-type mice.

“and induced endogenous TH17 cell differentiation.”

Hippocampal TH17 cells from learned-helpless mice express PD-1.

“and of follicular cells (CXCR5, PD-1)”

• Also stated in: § TFH-17-like cells accumulate in the hippocampus of learned-helpless mice · plain

  “There was a significant increase of the percent of TFH-17-like cells expressing PD-1 in learned-helpless mice (Fig 6A-B)”

Hippocampal TH17 cells from learned-helpless mice express CCR6.

“Hippocampal TH17 cells from learned-helpless mice expressed markers of pathogenic TH17 cells (CCR6, IL-23R)”

• Also stated in: § Hippocampal TH17 cells express CCR6 and IL-23R after learned-helplessness. · plain

  “the population of hippocampal TH17 cells expressing CCR6 was higher in learned-helpless mice than in resilient and unshocked mice (Fig 4G).”

CCR6-deficient TH17 cells have increased expression of PD-1.

“which was associated with increased expression of PD-1 in CCR6-deficient TH17 cells.”

The Treg population is unchanged by learned-helplessness in the hippocampus and prefrontal cortex.

“the TREGS population was unchanged by learned-helplessness in these brain regions (Fig 1F)”

Adoptively transferred TH17 cells into Rag2−/− mice increase susceptibility to learned helplessness.

“Adoptively transferred TH17 cells into Rag2−/− mice that are devoid of endogenous T cells increased susceptibility to learned helplessness”

• Also stated in: § TH17 cells but not TH1 cells promote depressive-like behaviors · plain

  “TH17 or TH1 cells adoptively transfer into male Rag2−/− mice revealed that only TH17 cells, but not TH1 cells, significantly increased susceptibility to learned-helplessness (Fig 1B).”

TH17 and TH1 cells do not differ in the cerebellum between non-depressed and depressed learned-helpless mice.

“There were no differences in TH17 and TH1 cells in the cerebellum between the ND and D groups (Fig S1B-C).”

Knockout of CCR6 blocks TH17 cells from promoting learned helplessness.

“Knockout of CCR6 blocked TH17 cells from promoting learned helplessness”

Administration of Tregs does not change susceptibility to learned-helplessness.

“administration of TH17 cells, but not TH1 cells or TREGS, promoted susceptibility to learned-helplessness depressive-like behavior”

• Also stated in: § TH17 cells accumulate in the hippocampus and the prefrontal cortex (PFC) after induction of learned-helplessness. · plain

  “Moreover, TREGS transfer did not change susceptibility to learned-helplessness (Fig S2).”

In wild-type mice, adoptively transferred TH17 cells accumulate in the hippocampus of learned-helpless mice.

“in wild-type mice, adoptively transferred TH17 cells accumulated in the hippocampus of learned-helpless mice”

• Also stated in: § Peripheral CD4+cells infiltrate the hippocampus after learned-helplessness · hedged

  “TH17 cells in the hippocampus after learned-helplessness originated predominantly from the donor cells in mice receiving CD45.1 TH17 cells, suggesting that adoptively transferred TH17 cells after learned-helplessness infiltrated the hippocampus (Fig 2D).”

Hippocampal TH17 cells from learned-helpless mice express IL-23R.

“Hippocampal TH17 cells from learned-helpless mice expressed markers of pathogenic TH17 cells (CCR6, IL-23R)”

• Also stated in: § Hippocampal TH17 cells express CCR6 and IL-23R after learned-helplessness. · plain

  “the expression of another marker of pathogenic TH17 cells, IL-23R, was higher in IL-17A+CD4+cells in the hippocampus of learned-helpless mice than in resilient mice or unshocked mice (Fig 4I).”

TH1 cells do not accumulate in the hippocampus of learned-helpless mice.

“There was a significant increase of TH17 cells (Fig 1D) but not TH1 cells (Fig 1E) in the hippocampus of mice exhibiting learned-helplessness”

TH17 cells accumulate in the hippocampus of learned helpless mice.

“accumulated in the hippocampus of learned helpless mice.”

• Also stated in: § TH17 cells accumulate in the hippocampus and the prefrontal cortex (PFC) after induction of learned-helplessness. · plain

  “There was a significant increase of TH17 cells (Fig 1D) but not TH1 cells (Fig 1E) in the hippocampus of mice exhibiting learned-helplessness”

Hippocampal TH17 cells from learned-helpless mice express CXCR5.

“and of follicular cells (CXCR5, PD-1)”

• Also stated in: § TFH-17-like cells accumulate in the hippocampus of learned-helpless mice · plain

  “TFH cells (CXCR5+CD4+) were enriched in the hippocampi of learned-helpless mice compared to resilient or unshocked mice (Fig 5A-B).”

Most Rag2−/− mice given undifferentiated CD4 cells did not exhibit learned-helplessness in the reduced intensity paradigm.

“Most Rag2−/− mice given undifferentiated CD4 cells did not exhibit learned-helplessness in the reduced intensity paradigm (Fig 1A-B)”

The population of hippocampal CD4+ cells expressing GFP was 2-fold higher in learned-helpless mice compared to resilient mice.

“the population of hippocampal CD4+cells expressing GFP, representing the induced host TH17 cells, was 2-fold higher in the learned-helpless mice compared to resilient mice, indicating a depression-associated induction of host hippocampal TH17 cells (Fig 3D).”

Expression of IL-23R was higher in IL-17A+CD4+ cells in the hippocampus of learned-helpless mice than in resilient or unshocked mice.

“the expression of another marker of pathogenic TH17 cells, IL-23R, was higher in IL-17A+CD4+cells in the hippocampus of learned-helpless mice than in resilient mice or unshocked mice (Fig 4I).”

TH1 cells accumulate in the prefrontal cortex after learned-helplessness.

“whereas both TH17 and TH1 cells accumulated in the PFC.”

81% of RORγT+/GFP mice receiving TH17 cells developed learned-helpless compared to 33% receiving undifferentiated CD4+ cells.

“administration of wild-type TH17 cells restored learned-helplessness susceptibility of RORγT+/GFP mice, as 81% of RORγT+/GFP mice receiving TH17 cells developed learned-helpless compared to 33% of RORγT+/GFP mice receiving undifferentiated CD4+cells (Fig 3A-B).”

mRNA levels of 5 factors were increased and 2 factors were decreased in the hippocampus of learned-helpless mice compared to resilient mice using a cut-off difference of 4-fold.

“we found that the mRNA levels of 5 factors were increased and 2 factors were decreased in the hippocampus of learned-helpless mice compared to resilient mice using a cut-off difference of 4-fold (Fig 4B).”

CD4+ cells found in the hippocampus after learned-helplessness were predominantly from host mice (CD45.2) after receiving CD45.1 TH17 cells.

“the CD4+ cells found in the hippocampus after learned-helplessness were predominantly from the host mice (CD45.2) after receiving CD45.1 TH17 cells (Fig 2A).”

IL-27 and Bcl-6 mRNA are not different between learned-helpless, resilient, and unshocked mice.

“However, two other TFH cell markers, IL-27 and Bcl-6, were not different between groups (Fig 4E-F).”

There was no difference in the percent of TH17 cells present in the hippocampus between learned-helpless and resilient mice.

“There was no difference in the percent of TH17 cells present in the hippocampus between learned-helpless and resilient mice, indicating that the migration of the donor TH17 cells to the hippocampus was induced by stress but was independent of the depressive status of the mouse (Fig 3C).”

Hippocampal levels of CD45.1+CD4+ cells were similar between mice that received undifferentiated CD4 cells or TH17 cells.

“hippocampal levels of CD45.1+CD4+ cells were similar between mice that received undifferentiated CD4 cells or TH17 cells, suggesting that the infiltration of CD4 cells is independent of their differentiation status (Fig 2C).”

In learned-helpless mice, hippocampal IL-17A mRNA levels were 1.65-fold levels of resilient or unshocked mice.

“in learned-helpless mice hippocampal IL-17A mRNA levels were 1.65-fold levels of resilient or unshocked mice (Fig 4A).”

Administration of wild-type TH17 cells restored learned-helplessness susceptibility of RORγT+/GFP mice.

“administration of wild-type TH17 cells restored learned-helplessness susceptibility of RORγT+/GFP mice, as 81% of RORγT+/GFP mice receiving TH17 cells developed learned-helpless compared to 33% of RORγT+/GFP mice receiving undifferentiated CD4+cells (Fig 3A-B).”

Without foot shocks, transferred TH17 cells did not accumulate in the hippocampus.

“Also, without foot shocks transferred TH17 cells did not accumulate in the hippocampus (Fig 3C).”

Spleen GFP+CD4+ cells were not different between learned-helpless and resilient mice.

“spleen GFP+CD4+cells were not different between learned-helpless and resilient mice (Fig 3E-F).”

Hippocampal CCL20 mRNA was 5-fold higher in learned-helpless mice compared to resilient or unshocked mice.

“hippocampal CCL20, the CCR6 ligand, mRNA was 5-fold higher in learned-helpless mice compared to resilient mice or unshocked mice (Fig 4H)”

Induction of GFP+CD4+ cells was restricted to mice receiving foot shocks.

“the induction of GFP+CD4+cells was restricted to mice receiving foot shocks, as CD4+cells from non-shocked mice did not express hippocampal GFP whether or not they received TH17 cells.”

In the spleen, TFH-17-like cells originated from the host after transfer of CD45.1-expressing CD4+ cells.

“In the spleen, the TFH-17-like cells originated from the host after transfer of CD45.1-expressing CD4+cells, and from the donor after transfer of CD45.1-expressing TH17 cells.”

There was no difference in IL-21 expression by TFH-17-like cells between learned-helpless and resilient mice.

“There was no difference in IL-21 expression by TFH-17-like cells between learned-helpless and resilient mice (Fig 5M-N)”

TH1 cell adoptive transfer did not promote learned-helplessness.

“Although there is some evidence of an association of TH1 cells and/or TH1 cell-derived cytokines with depression (Beurel et al., 2013; Myint et al., 2005), TH1 cell adoptive transfer did not promote learned-helplessness, as did TH17 cells, even though both TH17 and TH1 cells were elevated in the brains of learned-helpless mice (Beurel et al., 2013) (Fig 1).”

CCR6-deficient TH17 cells did not promote learned-helplessness.

“This is supported by our evidence that CCR6-deficient TH17 cells did not promote learned-helplessness even though they differentiated similarly to wild-type CD4+cells, suggesting that CCR6 confers pathogenicity.”

Hippocampal TH17 cells in learned-helpless mice express CXCR5.

“Characterization of hippocampal TH17 cells in learned-helpless mice revealed that they express CCR6 and IL-23R, and, more surprisingly, the follicular cell marker CXCR5.”

There was a significant increase of the percent of TFH-17-like cells expressing PD-1 in learned-helpless mice.

“There was a significant increase of the percent of TFH-17-like cells expressing PD-1 in learned-helpless mice (Fig 6A-B)”

In mice receiving CCR6-knocked out TH17 cells, 20% exhibited learned-helplessness compared to 80% of mice receiving TH17 cells.

“In mice receiving CCR6-knocked out TH17 cells, only 20% of the mice exhibited learned-helplessness compared to 80% of mice receiving TH17 cells (Fig 8I), confirming the requirement of CCR6 to promote susceptibility to learned-helplessness.”

At least 2 lineages of TH17 cells are present in the hippocampus after learned-helplessness.

“We found that at least 2 lineages of TH17 cells (although we did not directly test for the presence of memory cells) are present in the hippocampus after learned-helplessness.”

Hippocampal CD4+ cells not expressing IL-17A but expressing CXCR5 and CCR6 or IL-23R are similarly present in learned-helpless and resilient mice.

“Moreover, hippocampal CD4+cells not expressing IL-17A but expressing CXCR5 and CCR6 or IL-23R were similarly present in learned-helpless and resilient mice (Fig 6K-N), showing that hippocampal TFH-17-like cells express CCR6 and IL-23R.”

In the spleen, TFH-17-like cells originated from the donor after transfer of CD45.1-expressing TH17 cells.

“In the spleen, the TFH-17-like cells originated from the host after transfer of CD45.1-expressing CD4+cells, and from the donor after transfer of CD45.1-expressing TH17 cells.”

Learned-helplessness is associated with the hippocampal accumulation of TFH-17-like cells.

“In particular, we found that learned-helplessness is associated with the hippocampal accumulation of TFH-17-like cells, and that CCR6 is a critical mediator of pathogenicity in TH17-dependent learned-helplessness, which may provide potential new avenues for treatment.”

Increase of PD-1 expression in hippocampal TH17 cells was associated with resilience to learned-helplessness in mice receiving CCR6-deficient TH17 cells.

“Associated with the resilience to learned-helplessness of mice receiving CCR6-deficient TH17 cells was an increase of PD-1 expression in hippocampal TH17 cells.”

Hippocampal TH17 cells express higher levels of PD-1 in mice that received CCR6-knocked out TH17 cells.

“However, hippocampal TH17 cells express higher level of the follicular cell marker PD-1 in the mice that received CCR6-knocked out TH17 cells (Fig 8K), suggesting that PD-1 might be regulated by the pathogenic marker CCR6.”

The pro-depressive capacity of donor TH17 cells depends on the induction of endogenous TH17 cells.

“Additionally, using RORγt-GFP reporter mice, we found that the pro-depressive capacity of donor TH17 cells also depends on the induction of endogenous TH17 cells.”

TFH cells expressing IL-17A were increased in the hippocampi of learned-helpless mice.

“TFH cells expressing IL-17A were increased in the hippocampi of learned-helpless mice (Fig 5C-D)”

Hippocampal TFH-17-like cells arise from the host after adoptive transfer of CD45.1-expressing CD4+ cells or CD45.1-expressing TH17 cells, as they express mostly CD45.2.

“Moreover, using an adoptive transfer approach, we found that these TFH-17-like cells arise from the host, as TFH-17-like cells in the hippocampus express mostly CD45.2 whether they received CD45.1-expressing CD4+cells or CD45.1-expressing TH17 cells (Fig 7).”

Percent of TFH-17-like cells expressing CCR7 was similar between learned-helpless and resilient mice.

“the percent of TFH-17-like cells expressing BCL-6 (Fig 6E-F) or CCR7 (Fig 6C-D) was similar between learned-helpless and resilient mice”

Treg transfer did not affect susceptibility to learned-helplessness.

“Similar to TH1 cells, TREGS transfer did not affect susceptibility to learned-helplessness, suggesting that TREGS suppressive immune function is not sufficient to block the development of learned-helplessness.”

There was no difference in the percent of TH17 cells in the hippocampus between mice receiving wild-type or CCR6-deficient TH17 cells.

“However, we did not observe any difference in the percent of TH17 cells in the hippocampus between mice receiving wild-type or CCR6-deficient TH17 cells, suggesting that the hippocampal recruitment of CCR6-expressing TH17 cells during learned-helplessness was not driving the behavior.”

Hippocampal TFH-17-like cells expressing IL-23R are enriched in learned-helpless mice compared with resilient mice.

“There was an enrichment in hippocampal TFH-17-like cells expressing CCR6 (Fig 6G-H) and IL-23R (Fig 6I-J) in learned-helpless mice compared with resilient mice.”

Hippocampal TFH-17-like cells expressing CCR6 are enriched in learned-helpless mice compared with resilient mice.

“There was an enrichment in hippocampal TFH-17-like cells expressing CCR6 (Fig 6G-H) and IL-23R (Fig 6I-J) in learned-helpless mice compared with resilient mice.”

Mice receiving CXCR5-deficient TH17 cells were susceptible to learned-helplessness similar to mice receiving wild-type TH17 cells.

“Mice receiving CXCR5-deficient TH17 cells were susceptible to learned-helplessness similar to mice receiving wild-type TH17 cells, suggesting that CXCR5 was not required to promote susceptibility to learned-helplessness (Fig S4).”

• Also stated in: § Discussion · hedged

  “The role of CXCR5 in TH17 cells during depression is less clear than that of CCR6 and IL-23R because there was not a change in susceptibility to learned-helplessness after transfer of CXCR5-deficient TH17 cells, which does not exclude the possibility that CXCR5 is involved in the recruitment of TH17 cells to the hippocampus in conjunction with CCR6.”

Percent of TFH-17-like cells expressing BCL-6 was similar between learned-helpless and resilient mice.

“the percent of TFH-17-like cells expressing BCL-6 (Fig 6E-F) or CCR7 (Fig 6C-D) was similar between learned-helpless and resilient mice”

IL-21 was elevated in activated ICOS+ TFH-17-like cells in the hippocampus of learned-helpless mice.

“IL-21 was elevated in activated ICOS+ TFH-17-like cells in the hippocampus of learned-helpless mice, suggesting that only activated TFH-17-like cells express more IL-21 (Fig 5O-P).”

In mice receiving CCR6-knocked down TH17 cells, 30% exhibited learned-helplessness compared with 70% of mice receiving TH17 cells transfected with a scrambled siRNA.

“In mice receiving CCR6-knocked down TH17 cells, only 30% exhibited learned-helplessness compared with 70% of mice receiving TH17 cells transfected with a scrambled siRNA (siSCR) (Fig 8B).”

There was not an increase of TFH cells expressing IFNγ (TFH-1-like cells) in the hippocampi of learned-helpless mice.

“or of TFH cells expressing IFNγ (TFH-1-like cells) (Fig 5G-H), compared with resilient or unshocked mice.”

There was not an increase of TH17 cells not expressing CXCR5 in the hippocampi of learned-helpless mice.

“but there was not an increase of TH17 cells not expressing CXCR5 (Fig 5E-F)”

TFH cells (CXCR5+CD4+) were enriched in the hippocampi of learned-helpless mice compared to resilient or unshocked mice.

“TFH cells (CXCR5+CD4+) were enriched in the hippocampi of learned-helpless mice compared to resilient or unshocked mice (Fig 5A-B).”

The hippocampal cells are TFH-17-like cells.

“indicating that the hippocampal cells are TFH-17-like cells.”

Increased peripheral TH17 cells are capable of modulating depression-like behavior.

“demonstrating that increased peripheral TH17 cells are capable of modulating depression-like behavior.”

Depression-like behaviors are selectively facilitated by TH17 cells.

“these results reinforce the conclusion that depression-like behaviors are selectively facilitated by TH17 cells”

There is a depression-associated induction of host hippocampal TH17 cells.

“the population of hippocampal CD4+cells expressing GFP, representing the induced host TH17 cells, was 2-fold higher in the learned-helpless mice compared to resilient mice, indicating a depression-associated induction of host hippocampal TH17 cells (Fig 3D).”

The CCL20/CCR6 axis is activated in hippocampal TH17 cells.

“suggesting that the CCL20/CCR6 axis is activated in hippocampal TH17 cells.”

Infiltration of CD4 cells into the hippocampus is independent of their differentiation status.

“hippocampal levels of CD45.1+CD4+ cells were similar between mice that received undifferentiated CD4 cells or TH17 cells, suggesting that the infiltration of CD4 cells is independent of their differentiation status (Fig 2C).”

Host TH17 cells were induced and accumulated in the hippocampus after TH17-associated induction of learned-helplessness.

“This demonstrated that host TH17 cells were induced and accumulated in the hippocampus after TH17-associated induction of learned-helplessness.”

Patients with autoimmune diseases with elevated TH17 cells often exhibit comorbid depression.

“patients with autoimmune diseases with elevated TH17 cells often exhibit comorbid depression (Kurd et al., 2010; Patten et al., 2017).”

• cites Kurd et al., 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Patten et al., 2017 sourceNot checked — no full text of the source

Administration of IL-17A in rodents promotes depressive-like behaviors.

“administration of IL-17A in rodents promotes depressive-like behaviors (Nadeem et al., 2017)”

• cites Nadeem et al., 2017 sourceNot checked — no full text of the source

Hippocampal recruitment of CCR6-expressing TH17 cells during learned-helplessness was not driving the behavior.

“However, we did not observe any difference in the percent of TH17 cells in the hippocampus between mice receiving wild-type or CCR6-deficient TH17 cells, suggesting that the hippocampal recruitment of CCR6-expressing TH17 cells during learned-helplessness was not driving the behavior.”

TFH-17-like cells are the primary pathogenic cells in learned-helplessness.

“Here we report the selective modification by TH17 cells, but not TH1 cells or TREGS, of susceptibility to learned-helplessness and report the localization and characteristics of hippocampal TH17 cells in learned-helpless mice, which indicates that TFH-17-like cells are the primary pathogenic cells.”

PD-1 might be regulated by CCR6.

“However, hippocampal TH17 cells express higher level of the follicular cell marker PD-1 in the mice that received CCR6-knocked out TH17 cells (Fig 8K), suggesting that PD-1 might be regulated by the pathogenic marker CCR6.”

TH17 cells, but not TH1 cells or Tregs, selectively modify susceptibility to learned-helplessness.

“Here we report the selective modification by TH17 cells, but not TH1 cells or TREGS, of susceptibility to learned-helplessness and report the localization and characteristics of hippocampal TH17 cells in learned-helpless mice, which indicates that TFH-17-like cells are the primary pathogenic cells.”

• Also stated in: § Discussion · plain

  “Modulation of susceptibility to learned-helplessness was limited to TH17 cells.”

CCR6 is required to promote susceptibility to learned-helplessness.

“In mice receiving CCR6-knocked out TH17 cells, only 20% of the mice exhibited learned-helplessness compared to 80% of mice receiving TH17 cells (Fig 8I), confirming the requirement of CCR6 to promote susceptibility to learned-helplessness.”

Treg suppressive immune function is not sufficient to block the development of learned-helplessness.

“Similar to TH1 cells, TREGS transfer did not affect susceptibility to learned-helplessness, suggesting that TREGS suppressive immune function is not sufficient to block the development of learned-helplessness.”

CCR6 confers pathogenicity to TH17 cells in learned-helplessness.

“This is supported by our evidence that CCR6-deficient TH17 cells did not promote learned-helplessness even though they differentiated similarly to wild-type CD4+cells, suggesting that CCR6 confers pathogenicity.”

TH1 cells alone are not sufficient to promote learned-helplessness.

“These results suggest that TH1 cells alone are not sufficient to promote learned-helplessness, although they may play a role in conjunction with other depression-inducing factors.”

Donor TH17 cells reach the hippocampus after stress.

“Examining whether the accumulated TH17 cells in the hippocampus developed there or migrated, our evidence that CD45.1+ donor TH17 cells were found in the hippocampus of CD45.2 recipient mice after learned-helplessness indicates that donor TH17 cells reach the hippocampus after stress.”

TH17 cells (IL-17A+) accumulated in the hippocampus of learned-helpless mice are actually TFH-17-like cells.

“These results indicate that the TH17 cells (IL-17A+) accumulated in the hippocampus of learned-helpless mice are actually TFH-17-like cells.”

CXCR5 expression in TH17 cells is not required to promote susceptibility to learned-helplessness.

“Mice receiving CXCR5-deficient TH17 cells were susceptible to learned-helplessness similar to mice receiving wild-type TH17 cells, suggesting that CXCR5 was not required to promote susceptibility to learned-helplessness (Fig S4).”

Hippocampal TFH-17-like cells associated with learned-helplessness have unique properties compared to peripheral TFH cells.

“Although the role of CXCR5 in promoting depressive-like behavior needs to be further explored, the fact that some follicular markers (PD-1 and CXCR5), but not all (Bcl-6, CCR7), are increased in hippocampal TH17 cells in learned-helpless mice suggests that these hippocampal TFH-17-like cells associated with learned-helplessness have unique properties compared to peripheral TFH cells.”

CCR6 is a critical mediator of pathogenicity in TH17-dependent learned-helplessness.

“In particular, we found that learned-helplessness is associated with the hippocampal accumulation of TFH-17-like cells, and that CCR6 is a critical mediator of pathogenicity in TH17-dependent learned-helplessness, which may provide potential new avenues for treatment.”

PD-1 might contribute to the hippocampal follicular cell phenotype of TFH-17-like cells in learned-helpless mice.

“suggesting that PD-1 might contribute to the hippocampal follicular cell phenotype of the TFH-17-like cells in learned-helpless mice.”

This study identified the selective pathogenicity of the TH17 subtype of T cells.

“Altogether this study identified the selective pathogenicity of the TH17 subtype of T cells and identified novel characteristics of hippocampal TH17 cells associated with learned-helplessness.”

Only activated TFH-17-like cells express more IL-21.

“IL-21 was elevated in activated ICOS+ TFH-17-like cells in the hippocampus of learned-helpless mice, suggesting that only activated TFH-17-like cells express more IL-21 (Fig 5O-P).”