CD4+T cells confer anxiolytic and antidepressant-like effects, but enhance fear memory processes in Rag2−/−mice
Open accessAbstract
Accumulating evidence supports a role of T cells in behavioral stress responsiveness. Our laboratory previously reported that lymphocyte deficient Rag2(-/-) mice on a BALB/c background display resilience to maladaptive stress responses when compared with immune competent mice in the predator odor exposure (POE) paradigm, while exhibiting similar behavior in a cued fear-conditioning (FC) paradigm. In the present study, Rag2(-/-) mice on a C57BL/6 background were assessed in the same behavioral paradigms, as well as additional tests of anxiety and depressive-like behavior. Furthermore, the effects of naïve CD4(+ ) T cells were evaluated by adoptive transfer of functional cells from nonstressed, wild-type donors to Rag2(-/-) mice. Consistent with our prior results, Rag2(-/-) mice displayed an attenuated startle response after POE. Nevertheless, reconstitution of Rag2(-/-) mice with CD4(+ ) T cells did not modify startle reactivity. Additionally, in contrast with our previous findings, Rag2(-/-) mice showed attenuated fear responses in the FC paradigm compared to wild-type mice and reconstitution with CD4(+ ) T cells promoted fear learning and memory. Notably, reconstitution with CD4(+ ) T cells had anxiolytic and antidepressant-like effects in Rag2(-/-) mice that had not been previously stressed, but had no effect after POE. Taken together, our results support a role of CD4(+ ) T cells in emotionality, but also indicate that they may promote fear responses by enhancing learning and memory processes.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CD4+ cells modulate mood and learning and memory.
“CD4+ cells modulate mood and learning and memory, actions that mainly have been demonstrated using lymphopenic mice, such as T cell- and B cell-deficient Rag2−/− mice, that were replenished with adoptive transfer of splenocytes or lymphoid cells (Brachman et al., 2015; Clark et al., 2016; Filiano et al., 2017).”
From Distinct characteristics of hippocampal pathogenic th17 cells in a mouse model of depression (2018) · cites this paper as Clark et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., Cohen, H., Kipnis, J., & Schwartz, M. (2006) · Nature Neuroscience · doi:10.1038/nn1629 · Cited by 1,209 · see citing works
Wolf, S. A., Steiner, B., Akpinarli, A., Kammertoens, T., Nassenstein, C., Braun, A., Blankenstein, T., & Kempermann, G. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0801218 · Cited by 329 · see citing works
Inflammatory T helper 17 cells promote depression-like behavior in mice
Beurel, E., Harrington, L. E., & Jope, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.09.021 · Cited by 254 · see citing works
Adaptive immunity affects learning behavior in mice
Brynskikh, A., Warren, T., Zhu, J., & Kipnis, J. (2008) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2007.12.008 · Cited by 221 · see citing works
Lymphocytes from Chronically Stressed Mice Confer Antidepressant-Like Effects to Naive Mice
Brachman, R. A., Lehmann, M. L., Maric, D., & Herkenham, M. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2278-14.2015 · Cited by 130 · see citing works
Flagged first, then by citations
Research works printed but not linked: 20
- Brod S Rattazzi L Piras G D’Acquisto F ‘As above, so below’ examining the interplay between emotion and the immune system Immunology 2014 143 3 311 8 24943894 PMC4212945
- Chun JJ Schatz DG Oettinger MA Jaenisch R Baltimore D The recombination activating gene-1 (RAG-1) transcript is present in the murine central nervous system Cell 1991 64 1 189 200 1986864
- Clark SM Michael KC Klaus J Mert A Romano-Verthelyi A Sand J Tonelli LH Dissociation between sickness behavior and emotionality during lipopolysaccharide challenge in lymphocyte deficient Rag2(−/−) mice Behav Brain Res 2015 278 74 82 25257108 PMC4369474
- Clark SM Sand J Francis TC Nagaraju A Michael KC Keegan AD Kusnecov A Gould TD Tonelli LH Immune status influences fear and anxiety responses in mice after acute stress exposure Brain Behav Immun 5 2014 38 192 201 24524915 PMC3989422
- Cohen H Ziv Y Cardon M Kaplan Z Matar MA Gidron Y Schwartz M Kipnis J Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells J Neurobiol 2006 66 6 552 63 16555237
- Cushman J Lo J Huang Z Wasserfall C Petitto JM Neurobehavioral changes resulting from recombinase activation gene 1 deletion Clin Diagn Lab Immunol 2003 10 1 13 8 12522033 PMC145286
- Derecki NC Cardani AN Yang CH Quinnies KM Crihfield A Lynch KR Kipnis J Regulation of learning and memory by meningeal immunity: a key role for IL-4 J Exp Med 2010 207 5 1067 80 20439540 PMC2867291
- Kim SJ Lee H Lee G Oh SJ Shin MK Shim I Bae H CD4+CD25+ regulatory T cell depletion modulates anxiety and depression-like behaviors in mice PloS one 2012 7 7 e42054 22860054 PMC3409145
- Kipnis J Cohen H Cardon M Ziv Y Schwartz M T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions Proc Natl Acad Sci U S A 2004 101 21 8180 5 15141078 PMC419577
- Kipnis J Gadani S Derecki NC Pro-cognitive properties of T cells Nat Rev Immunol 2012 12 9 663 9 22903149 PMC4032225
- Lewitus GM Cohen H Schwartz M Reducing post-traumatic anxiety by immunization Brain Behav Immun 2008 22 7 1108 14 18562161
- Lewitus GM Schwartz M Behavioral immunization: immunity to self-antigens contributes to psychological stress resilience Mol Psych 2009 14 5 532 6 18779818
- Lewitus GM Wilf-Yarkoni A Ziv Y Shabat-Simon M Gersner R Zangen A Schwartz M Vaccination as a novel approach for treating depressive behavior Biol Psych 2009 65 4 283 8 18722594
- McGowan PO Hope TA Meck WH Kelsoe G Williams CL Impaired social recognition memory in recombination activating gene 1-deficient mice Brain Res 2011 1383 187 95 21354115 PMC3436067
- Radjavi A Smirnov I Kipnis J Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire Brain Behav Immun 2014 35 58 63 24012647 PMC3858511
- Rattazzi L Piras G Ono M Deacon R Pariante CM D’Acquisto F CD4(+) but not CD8(+) T cells revert the impaired emotional behavior of immunocompromised RAG-1-deficient mice Transl Psych 2013 3 e280 PMC3731786 23838891
- Rilett KC Friedel M Ellegood J MacKenzie RN Lerch JP Foster JA Loss of T cells influences sex differences in behavior and brain structure Brain Behav Immun 2015 46 249 60 25725160
- Ron-Harel N Cardon M Schwartz M Brain homeostasis is maintained by “danger” signals stimulating a supportive immune response within the brain’s borders Brain Behav Immun 2011 25 5 1036 43 21182929
- Schwartz M Kipnis J A conceptual revolution in the relationships between the brain and immunity Brain Behav Immun 2011 25 5 817 9 21187141 PMC3074045
- Shinkai Y Rathbun G Lam KP Oltz EM Stewart V Mendelsohn M Charron J Datta M Young F Stall AM RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement Cell 1992 68 5 855 67 1547487
Cited by
Sorted by citations
Distinct characteristics of hippocampal pathogenic th17 cells in a mouse model of depression
Beurel, E., Lowell, J. A., & Jope, R. S. (2018) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2018.04.012 · Cited by 65 · see citing works
Inflamed brain: Targeting immune changes and inflammation for treatment of depression
Sakamoto, S., Zhu, X., Hasegawa, Y., Karma, S., Obayashi, M., Alway, E., & Kamiya, A. (2021) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13286 · Cited by 51 · see citing works
Sun, Z., Zhang, B., Zhou, J., Luo, Y., Zhu, X., Wang, Y., He, Y., Zheng, P., Zhang, L., Yang, J., et al. (2024) · Advanced Science · doi:10.1002/advs.202308393 · Cited by 20 · see citing works
- Authors
- Clark, S. M., Soroka, J. A., Song, C., Li, X., & Tonelli, L. H.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Clark, Sarah M.
- Venue
- Stress
- Publisher
- Informa UK Limited
- Published
- 2016-05-03
- Volume
- 19
- Issue
- 3
- Pages
- 303-311
- ISSN
- 1025-3890 (ISSN-L)
- 1607-8888
- PMC
- PMC4960826
- OpenAlex
- W2430149710
- Cited by
- 34
- References
- 5
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 4 · 2022: 7 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 7 · 2016: 1
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Stress (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (OppNet R01MH097676)
- Department of Veterans Affairs (VA Merit Review Award BX00935)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- CD4+ T cells, Rag2-deficient mice, anxiety-like behavior, antidepressant-like behavior, fear memory, fear conditioning, startle response, adoptive T cell therapy, immunodeficiency, stress resilience, emotionality
- MeSH terms
- Animals, Anxiety, Depression, DNA-Binding Proteins, Emotions, Fear, Memory, Reflex, Startle, CD4-Positive T-Lymphocytes, Mice, Knockout, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
