Regulatory CD8+CD122+ T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells

Abstract

Clinical stroke induces inflammatory processes leading to cerebral and splenic injury and profound peripheral immunosuppression. IL-10 expression is elevated during major CNS diseases and limits inflammation in the brain. Recent evidence demonstrated that transfer of IL-10+ B-cells reduced infarct volume in male C57BL/6J (wild-type, WT) recipient mice when given 24 h prior to or 4 h after middle cerebral artery occlusion (MCAO). The purpose of this study was to determine if passively transferred IL-10+ B-cells can exert therapeutic and immunoregulatory effects when injected 24 hours after MCAO induction in B-cell-sufficient male WT mice. The results demonstrated that IL-10+ B-cell treated mice had significantly reduced infarct volumes in the ipsilateral cortex and hemisphere and improved neurological deficits vs. Vehicle-treated control mice after 60 min occlusion and 96 h of reperfusion. The MCAO-protected B-cell recipient mice had less splenic atrophy and reduced numbers of activated, inflammatory T-cells, decreased infiltration of T-cells and a less inflammatory milieu in the ischemic hemispheres compared with Vehicle-treated control mice. These immunoregulatory changes occurred in concert with the predominant appearance of IL-10-secreting CD8+CD122+ Treg cells in both the spleen and the MCAO-affected brain hemisphere. This study for the first time demonstrates a major neuroprotective role for IL-10+ B-cells in treating MCAO in male WT mice at a time point well beyond the ~4 h tPA treatment window, leading to the generation of a dominant IL-10+CD8+CD122+ Treg population associated with spleen preservation and reduced CNS inflammation.

Partial MHC Constructs Treat Thromboembolic Ischemic Stroke Characterized by Early Immune Expansion

“…The decrease we see in B cell frequency in the spleen has also been observed at later time points in transient MCAO [8]. B cell subsets have been found to be protective in experimental stroke [25, 33, 34] and their decrease in the periphery could also exacerbate ischemic brain damage. Another hallmark of stroke is splenic atrophy [9].…”

Functional Role of Regulatory Lymphocytes in Stroke

“…56 A more recent experiment confirmed a potentially neuroprotective function of regulatory IL-10-producing B-cells after stroke by inducing CD8 + CD122 + Treg and ameliorating post-stroke neuroinflammation. 57 Taken together, the findings of previous studies not observing a major role for B-cells in the acute phase after stroke and more recent reports of a neuroprotective function of Breg in later secondary neuroinflammatory response might support an immunoregulatory effect of IL-10-secreting B-cells and their induction of CD8 + CD122 + Treg at later stages of post-stroke neuroinflammation. Considering the previously observed differences in natural Treg function between stroke models, it will be of interest for future studies to also investigate such a differential role for other regulatory lymphocytes, such as Breg and CD8 + CD122 + Treg.…”

PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation

“…An important additional feature of PD-L1 blockade that likely contributed to better MCAO outcomes is the induction of IL-10-secreting CD8 + CD122 + T-regulatory cells 29 that were significantly increased in both the spleen (Figure 5C) and the lesioned brain hemisphere (Figure 3D) after anti-PD-L1 therapy. The contribution of this CD8 + Treg population could account for the increased expression of Il-10 in the ischemic brain hemisphere (Figure 4B) and may be crucial for successful treatment of MCAO in the absence of increased levels of other protective anti-inflammatory cell populations, including CD4 + FoxP3 + Tregs 17, 22 and IL-10 + Bregs 16, 30 that appear to be downregulated by PD-L2 in the absence of PD-L1 11 .…”