Lymphocytes in neuroprotection, cognition and emotion: Is intolerance really the answer?

Graham A.W. Rook, Christopher A. Lowry, Charles L. Raison

Research output: Contribution to journalReview articlepeer-review

34 Scopus citations


Clinical, epidemiological and therapeutic studies indicate that some human depression is associated with proinflammatory cytokines, chronic inflammatory disorders, and inflammation-inducing lifestyle factors. Moreover depression can be induced by administration of proinflammatory cytokines, including IL-2 or IFN-α. However, recent studies in specific pathogen-free (SPF) rodents suggest a different-and potentially contradictory-relationship between immune processes and mental health. These studies suggest that effector T cells specific for central nervous system (CNS) antigens can assist recovery from an array of environmental insults ranging from nerve injury to psychological stress, while in contrast, regulatory T cells (Treg) oppose such recovery. Indeed, some reported effects of this so-called " protective autoimmunity" seem of direct relevance to depressive disorders. These findings pose a dilemma for those intending to manipulate inflammatory pathways as a treatment for depression. Should we administer anti-inflammatory treatments, or should we induce self-reactive T cells? We re-examine the rodent findings and outline immunological peculiarities of SPF rodents, the abnormal properties of their regulatory T cells, and the impact of gut microbiota. We find that " protective autoimmunity" is likely to be relevant only to very clean SPF animals that lack normal levels of activated T cells, CNS T cell traffic and mature Treg. The data indicate that even in SPF models the effectors of beneficial effects are not the proinflammatory autoimmune cells themselves, but rather unidentified regulatory cells. This reinterpretation of findings relevant to " protective autoimmunity" suggests that ongoing, and planned, clinical trials of anti-inflammatory strategies to treat depressive disorders are justified.

Original languageEnglish (US)
Pages (from-to)591-601
Number of pages11
JournalBrain, Behavior, and Immunity
Issue number4
StatePublished - May 2011
Externally publishedYes


  • Autoimmunity
  • IL-10
  • Immunoregulation
  • Neuroprotection
  • Treg

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience


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