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Yoshimura et al. Neuroimmunol Neuroinflammation 2020;7:264-76 I http://dx.doi.org/10.20517/2347-8659.2020.22 Page 269

T cell could serve as a therapeutic target for stroke. However, we should remain cautious that within one
week after stroke onset, the number of T cells in the brain is small and represents only a small fraction of
[19]
infiltrated mononuclear cells [Figure 1].
It has been reported that during the acute phase of stroke, Tregs infiltrate the brain, suppressing
neuroinflammation, therby reducing the severity of ischemic brain injury [60,66,67] . However, the significance
of Tregs in brain injury has become controversial [68,69] . Importantly, the number of Tregs in the brain at this
stage is extremely low (less than 100 cells/brain in mice), and antigen-specific activation and proliferation
of Tregs may not occur in such a short period (within 3 days), since it usually takes more than a week to
raise adaptive immunity in the host [Figures 1 and 2]. Thus, bystander effects, such as paracrine effects of
IL-10, may explain an anti-inflammatory role of Tregs at the acute phase.

ACCUMULATION OF BRAIN TREGS AT THE CHRONIC PHASE OF STROKE
It is thought that inflammation no longer plays an important role in neural damage and recovery at the
chronic phase of stroke (> 7 days after stroke onset). Inflammation is not clearly obvious at this stage.
However, compared to the acute phase, Tregs as well as other lymphocytes have been shown to accumulate
in substantial quantities in the brain at the chronic phase of the experimental stroke model [9-13] [Figures
1 and 2]. Infiltration of Tregs proceeds with slightly delayed kinetics compared with that of other T cells.
Tregs may also infiltrate the spinal cord parenchyma during the subacute to chronic phases in the spinal
+
[70]
cord injury model . Tregs consist of approximately 50% of CD4 T cells, and localize within and around
the cerebral infarction lesion. Outside the infarct core area, Tregs remain in close proximity to scar-forming
astrocytes and neuronal cells. Treg fractions in the brain are extremely higher that those in other lymphoid
+
organs such as the spleen and lymph nodes. Since CD8 T cells are also present, about 1/4 to 1/5 of T cells
in the brain are calculated as Tregs.

To determine the role of T cells in ischemic brain injury, mice were treated with FTY720 or anti-CD4
antibody during the chronic phase after stroke. Tregs can also be depleted by the use of Foxp3-diphtheria
[71]
toxin receptor (DTR) mice, where DTR is specifically expressed on Tregs . These treatments drastically
+
reduce the number of CD4 T cells including Tregs in the brain, delaying neurological recovery. These data
[9]
indicate that brain Tregs at the chronic phase are important for suppressing neurological symptoms .
[10]
Stubbe et al. observed no changes regarding neurologic outcome if they depleted Tregs through the use
[10]
of anti-CD25 antibody . Anti-CD25 antibody, however, may not be able to completely deplete Tregs,
[72]
possibly depleting pathogenic T cells as well . Other studies have also shown that brain Tregs play
neuroprotective roles during the late stage of stroke and spinal cord injury models [12,73] .
CHARACTERIZATION OF BRAIN TREGS
+
Tregs consist of approximately 10% of CD4 T cells, located within most lymphoid organs and blood,
moving to specific sites of inflammation after immunization. In addition, Tregs have recently been
discovered in various tissues besides lymphoid tissues, in steady state conditions as well as during injury.
These tissue-residing Tregs are now termed “tissue Tregs”, which have a limited TCR repertoire and
recognize the self-antigen characteristically expressed in each tissue. Such tissue Tregs exist in fats, muscles,
skin, lungs, and intestines, exhibiting similar phenotypes among organs, but are quite different from those
of lymphoid tissue [74-78] . The features common to various tissue Tregs are high expressions of Il10, Areg
(amphiregulin), Klrg1, Tigit, Il1rl1 (encoding ST2, IL-33 receptor), Ctla4, Irf4, Batf, and Gata3 and low
expressions of Bcl2, Tcf7, and Lef1 compared with lymphatic Tregs [74,79] . BATF is shown to be an important
[80]
regulator for Tregs to accumulate preferentially in several tissues . In addition to the common genes
expressed in various tissue Tregs, unique tissue-specific genes are also found in tissue Tregs namely Pparg
in fat Tregs. The microenvironment of each organ appears to determine the tissue-specific phenotypes of
tissue Tregs.