CON: Regulatory T Cells Are Protective in Ischemic Stroke
Christoph Kleinschnitz, MD; Heinz Wiendl, MD
F
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or many years ischemic stroke was regarded as a purely
thrombotic disease resulting from the occlusion of cerebral arteries and subsequent breakdown of energy supply
to neuronal tissues. Back in the late 1970, however, some
pioneers in experimental stroke research, above all John
Hallenbeck at the National Institute of Neurological Disorders
and Stroke recognized the existence of polymorphonuclear
leukocytes and macrophages in brain specimen from animals
and patients with cerebral ischemia, thereby establishing the
conceptual basis for the immunobiology of stroke.1 Since then
a plethora of experimental studies stressed the importance
of these typically innate immune cells in brain ischemia but
clinical trials testing, for example, neutrophil blocking agents,
ultimately bombed. Several years later Stoll and Jander2 from
Düsseldorf, Germany, were among the first to describe the
infiltration of T lymphocytes, which per definition belong to
the adaptive immune system, into ischemic brains of rodents.
Of note, this happened accidentally while searching for a central nervous system lesion paradigm devoid of inflammation
which could be used as control for experimental autoimmune
encephalomyelitis.
It is meanwhile well accepted that T cells exert deleterious
effects in brain ischemia. However, the functional relevance of
the different T cell subsets for stroke progression is less clear,
as is their pathological contribution at the different stages of
infarction (ie, acute versus chronic). In particular, a controversial dispute recently arose on the function of regulatory T cells
(Tregs) in the ischemic brain.
In a rather simplistic view, many people think about Tregs
as the good immune cells which without exception maintain immune tolerance and counteract tissue damage in a
variety of (neurological) diseases, such as multiple sclerosis. However, biology usually does not follow a plain black
and white dichotomy, and in most situations an exception
to the rule exists. In the case of Tregs this exception is ischemic stroke. Using a mouse model of selective Tregs depletion (Depletion of Regulatory T cells [DEREG] mice), we
could unambiguously show that Tregs are strong promoters
of ischemic neurodegeneration.3 Depletion of Tregs dramatically reduced infarct size and improved neurological function
24 hours after 60 minutes of transient middle cerebral artery
occlusion, and this protective phenotype was preserved at later
stages of infarct development (until day 7) and in models of
mild ischemic stroke. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with
the ischemic brain endothelium and platelets. Accordingly,
ablation of Tregs reduced microvascular thrombus formation
and improved cerebral reperfusion on stroke, reinforcing the
recently established concept of thrombo-inflammation. In
contrast, common immunoregulatory characteristics of Tregs,
such as cytokine release or modulation of other immune cell
populations, had no functional relevance.3
Apart from our study which was the first to report a detrimental Tregs effect in a primary nonimmunologic disease
model, there are currently 4 other studies that examined the
consequences of Tregs on stroke outcome in rodent models of
cerebral ischemia. Two of these described a protective role of
Tregs,4,5 whereas the remaining ones were neutral.6,7
What are the particular strengths of our investigation? First,
we introduced a genetic mouse model (DEREG) that allows
for the ablation of FoxP3+ Tregs with high specificity, while
most other groups used an anti-CD25 antibody to deplete
CD4+CD25+ T cells.4,5,7 There have been convincing reports
that this antibody induces shedding of the binding epitope
rather than depletion of the cells and the fact that CD25 is also
upregulated on activated T cells, as well as the existence of
CD25-negative Tregs subpopulations limits the interpretation
of the data. Second, Tregs depletion is reversible in DEREG
mice, hence bearing the unique possibility to use intrinsic phenotype rescue as a control. Finally, we validated our results
from DEREG mice by adoptive transfer experiments of Tregs
in Rag1−/− mice lacking T lymphocytes.
Li et al5 reported that exogenously applied Tregs induce
neuroprotection in stroke mainly by modulating the effector functions of neutrophils. Given that the true pathophysiological relevance of neutrophils in stroke has recently been
heavily tackled however,8 the findings should be interpreted
with caution. Also, the in vivo expansion of Tregs for clinical translation as suggested by the authors already produced
unforeseen adverse effects in a phase 1 trial.9 Here, an antibody directed against CD28 (TGN1412) induced a massive
cytokine storm in healthy volunteers. However, whether this
is also of relevance in the setting of ischemic stroke or when
using other approaches to expand Tregs is unknown so far.
Received March 12, 2013; accepted May 16, 2013.
From the Department of Neurology, University Clinic Würzburg, Würzburg, Germany (C.K.); Department of Neurology, University of Münster, Münster,
Germany (H.W.).
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 2 of a 3-part article.
Parts 1 and 3 appear on pages e84 and e85, respectively.
Correspondence to Christoph Kleinschnitz, MD, Department of Neurology, University Clinic Würzburg, Josef-Schneider Strasse 11, 97080 Würzburg,
Germany. E-mail [email protected]
(Stroke. 2013;44:e87-e88.)
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.113.001268
e87
e88 Stroke August 2013
Moreover, Tregs might take over different tasks in stroke and
their net biological effects probably depend on the stage of the
insult and the timing of application.
As it becomes increasingly clear that ischemic stroke is far
more than a simple vessel occlusive disease, the novel Basic
Science Controversy Section will hopefully help the stroke
community to develop new ideas that reach beyond the everlasting extension of time windows and vascular recanalization
or dubious neuroprotection strategies.
Disclosures
None.
References
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Key Words: Regulatory T cells ◼ Tregs ◼ stroke ◼ middle cerebral artery
occlusion ◼ inflammation ◼ thrombo-inflammation
CON: Regulatory T Cells Are Protective in Ischemic Stroke
Christoph Kleinschnitz and Heinz Wiendl
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2017
Stroke. 2013;44:e87-e88; originally published online July 2, 2013;
doi: 10.1161/STROKEAHA.113.001268
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