T Cells Contribute to Stroke-Induced Lymphopenia in Rats

Abstract

Stroke-induced immunodepression (SIID) results when T cell and non-T immune cells, such as B cells, NK cells and monocytes, are reduced in the peripheral blood and spleen after stroke. We investigated the hypothesis that T cells are required for the reductions in non-T cell subsets observed in SIID, and further examined a potential correlation between lymphopenia and High-mobility group protein B1 (HMGB1) release, a protein that regulates inflammation and immunodepression. Our results showed that focal ischemia resulted in similar cortical infarct sizes in both wild type (WT) Sprague Dawley (SD) rats and nude rats with a SD genetic background, which excludes the possibility of different infarct sizes affecting SIID. In addition, the numbers of CD68-positive macrophages in the ischemic brain did not differ between WT and nude rats. Numbers of total peripheral blood mononuclear cells (PBMCs) or splenocytes and lymphocyte subsets, including T cells, CD4+ or CD8+ T cells, B cells and monocytes in the blood and spleen, were decreased after stroke in WT rats. In nude rats, however, the total number of PBMCs and absolute numbers of NK cells, B cells and monocytes were increased in the peripheral blood after stroke; nude rats are athymic therefore they have few T cells present. Adoptive transfer of WT splenocytes into nude rats before stroke resulted in lymphopenia after stroke similar to WT rats. Moreover, in vitro T cell proliferation stimulated by Concanavalin A was significantly inhibited in WT rats as well as in nude rats receiving WT splenocyte adoptive transfer, suggesting that T cell function is indeed inhibited after stroke. Lastly, we demonstrated that stroke-induced lymphopenia is associated with a reduction in HMGB1 release in the peripheral blood. In conclusion, T cells are required for stroke-induced reductions in non-T immune cells and they are the most crucial lymphocytes for SIID.

T Cells and Cerebral Ischemic Stroke

“…T cells, Tregs, NK cells, B cells and monocytes 72 h after stroke, accompanied by a significant reduction in spleen weight [32]. Finally, we observed that dMCAO induced significant inhibition of the proliferative ability of splenocytes stimulated by T cell mitogen Concanavalin A [32]. These results serve to confirm that stroke induces lymphopenia,-likely contributing to an inhibition of immune function.…”

“…Earlier studies in experimental models of cerebral ischemia demonstrated that T cells were recruited and involved in the ischemic brain at later stages (3 days post-ischemia) [27][28][29] compared with the significantly increased infiltration of activated microglia/macrophages and neutrophils at earlier times (several minutes to hours post-ischemia) [29]. More recent studies including our results showed that within the first 24 h, T cells and their subsets were involved or recruited in the ischemic brain after focal ischemia in experimental animal models [5,7,24,[30][31][32][33]. Yilmaz et al [5] reported that CD4 ?…”

“…Interestingly, adoptive transfer of T cells resulted in attenuation of the increase in bacterial loads in the blood and lung observed in control MCAO mice, thereby implying that T cells are critical in resisting bacterial infections followed stroke [46]. We recently found that in T cell-deficient rats the total number of PBMCs and absolute numbers of B cells, NK cells, and monocytes were robustly increased after dMCAO compared with both naïve and sham surgery at 48 h and 72 h. This result is opposite from the reduction in numbers of immune cells post stroke in wild-type rats [32]. Furthermore, we found that spleen weight was not altered 72 h after stroke in these nude rats [32].…”

“…, CD8 ? T cells, Tregs, B cells, and monocytes in the peripheral blood of Sprague-Dawley rats 48 h and at 72 h following coagulation of the distal middle cerebral artery relative to naïve or sham surgery [32]. In the spleen, stroke also resulted in significant reduction in total number of splenocytes and absolute numbers of individual subsets, including T cells, CD4 ?…”

“…and CD8 ? T cell subsets were recruited and infiltrated in the ischemic hemisphere 24 and 72 h after stroke in distal MCAO model in rats [32,33]. Gelderblom et al [24] presented a neuroinflammatory time course following MCA occlusion in mice whereby T cells invade the injured brain within 24 h and reach a peak on day 3, followed by a gradual decline.…”