Regulatory T cells in MS lesions are anti-inflammatory: Regulation is no bad thing

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As with so much in life, an appropriate immune response is composed of checks and balances. Too much inflammation or too little regulation is a bad thing and can lead to life-threatening disease, such as asthma or autoimmune conditions including multiple sclerosis (MS). For the past 20 years, a primary focus for immunologists has been the study of regulatory T (Treg) cells. CD4+ Treg cells originally identified by their high and continued expression of the interleukin (IL) IL-2 receptor, CD25, were subsequently distinguished by the transcription factor FoxP3. Natural Treg cells derived from the thymus and inducible Treg cells generated in the periphery from CD4+ T cells, both have suppressive functions required to maintain tolerance, preventing autoimmunity and limiting inflammatory responses. The importance of these cell populations is evident through a vast amount of work demonstrating that in their absence, immune responses can become highly pathological.1
In view of this there is a real drive to utilize Treg cells in immunotherapy. Inhibition of Treg cell function to break tolerance for cancer treatment, or stimulation of Treg cell function on a cellular basis or by increasing numbers to induce tolerance and limit autoimmunity has enormous therapeutic potential. Such clinical promise was upended when it was discovered that under certain circumstances FoxP3+ Treg cells also co-express the transcription factor RORγt and secrete the proinflammatory cytokine IL-17A.2 How often and under what circumstances this occurs in vivo during disease remains a critical question if we are to harness their properties for immunotherapy.
A failure in Treg cells has been implicated in the induction of the autoimmune disease MS,3,4 and currently one of the most promising therapies aims to increase this population in the periphery.5,6 Yet recent studies investigating the stability of FoxP3+ T cells from peripheral blood of MS patients suggests that Treg cells are prone to interferon (IFN)-γ production and would, therefore, not be an ideal therapeutic target. Such studies are limited as they are analyzing circulating cells rather than FoxP3+ cells at the site of inflammation.7 In this issue of Immunologyand Cell Biology, Zandee et al.,8 using a novel tissue bank of post-mortem brain tissue from patients who have died of non-neurological causes provide significant evidence that Treg cells in MS lesions retain their regulatory suppressive function.
MS, is a demyelinating autoimmune disease that can encompass a broad set of pathologies and is, somewhat unsatisfyingly, defined as having two or more lesions in the central nervous system (CNS) separated in time and space that cannot be attributed to any other clinical cause. Lesions are caused by autoimmune T cells targeting the myelin sheath around neurons. Further classification of MS is achieved by determining disease progression. Most patients have relapsing remitting disease, in which symptoms hit sporadically followed by periods of healing in which little to no symptoms are apparent. The healing involves the remyelination of neurons, a reduction in inflammatory cells in the CNS and disappearance of lesions as observed by magenetic resonance imaging. This state is frequently followed by secondary progressive MS (SPMS) where symptoms worsen over time. Zandee and colleagues accessed the UK Multiple Sclerosis Tissue Bank of post-mortem brain tissue from secondary progressive MS patients and control individuals who died of non-neurological causes. Of 10 patients with lesions, 7 had Treg cells present as identified by the co- expression of FoxP3 and the production of IL-10 by Treg cells. This type of tissue bank allows analysis of a greater range of lesions than tissue from patients who have died due to MS-related pathology.

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