Elevated pro-inflammatory CD4⁺CD28^- lymphocytes and stroke recurrence and death

Objective: To determine if the CD4⁺CD28^- T-cell subset is expanded in patients with recurrent stroke or death after acute ischemic stroke. This subset of the peripheral blood T-cell lymphocyte population has a strong proinflammatory and tissue-damaging potential. Methods: Consecutive patients within the first 48 hours of ischemic stroke were prospectively studied. Peripheral blood CD4⁺CD28^- cells were quantified by flow cytometry. The study endpoint was recurrent stroke or death from any cause during 1 year of follow-up. Results: One hundred six patients (mean age 75.0 ± 13.5 years; 50 women) were studied. The median CD4⁺CD28^- cell count was 4.5% (range 0.2 to 72.2%). Twenty-seven endpoints (10 recurrent strokes and 17 deaths) occurred during follow-up. Stroke recurrence/death rates were significantly associated with increasing CD4⁺CD28^- counts, rising from 14.2% in patients with CD4⁺CD28^- levels of <1.0 to 48.1% for those with CD4⁺CD28^- counts of >8.0% (p = 0.003, Cochran linear test of trend). Higher CD4⁺CD28^- counts were also present in patients with a history of prior stroke (p = 0.03). After adjustment for age, admission NIH Stroke Scale score, prior stroke, and atrial fibrillation, CD4⁺CD28^- counts of >8.0% were associated with a cumulative hazard ratio of 5.81 (95% CI: 1.58 to 21.32) for stroke recurrence or death. Conclusions: Rising counts of circulating CD4⁺CD28 ^- cells are associated with an increasing risk of stroke recurrence and death, in addition to an observed association with prior stroke. Expansion of this T-cell subset presumably represents a biomarker and possibly a contributory pathogenic mechanism of recurrent stroke and death after ischemic stroke.