Aurora Semerano, MD
Schulze J, Gellrich J, Kirsch M, Dressel A, Vogelgesang A. Central Nervous System-Infiltrating T Lymphocytes in Stroke Are Activated via Their TCR (T-Cell Receptor) but Lack CD25 Expression. Stroke. 2021;52:2939–2947.
Leukocytes from peripheral circulation infiltrate the ischemic brain within hours to days after stroke, and they can contribute to secondary tissue damage, as well as to the subsequent processes of repair and recovery. T lymphocytes are also implied in this response. However, it remains unclear which mechanism of lymphocyte activation plays the most relevant role after stroke: Indeed, both antigen-specific T lymphocytes (reacting against brain antigens) and antigen-independent mechanisms (driven by pro-inflammatory mediators) have been described. These previous studies were mostly conducted with ablative approaches, that’s to say in T-cell-deficient experimental models or upon inhibition of lymphocyte infiltration into the brain.
In this study by Schulze et al. recently published in Stroke, the authors aimed at exploring the relevance of antigen-specific or antigen-nonspecific lymphocyte activation upon stroke by using a distinct approach: They performed experimental stroke in a Nur77GFP transgenic mouse model that expresses a fluorescent protein upon activation via the TCR (T-cell receptor), allowing the differentiation of activation mode in a natural repertoire of immune cells and antigens. Strong infiltration of T lymphocytes into the ischemic hemisphere was detected, and peaked on day 4 after stroke. They found that, in contrast with the circulating counterparts, T lymphocytes infiltrating the ischemic brain predominantly displayed antigen-specific activation, as suggested by the co-expression of GFP with the activation markers CD69, PD-1, and CD25. They also observed that PD-1 (an immune checkpoint able to inhibit the inflammatory response) was upregulated within the brain, whereas CD25 (the subunit of the IL-2 receptor) was not.
It is interesting to note that, despite the disruption of the blood-brain barrier and the release of brain antigens after cerebral ischemia, stroke patients do not develop inflammatory autoimmunity, as seen in multiple sclerosis. The authors argue that the strong expression of PD-1 and the lack of CD25 upregulation may account for this difference, and they speculate that it might represent a self-protecting mechanism to maintain the suppression of the auto-immune response into the brain. The clinical relevance of this response needs to be further investigated. It would be interesting to explore whether antigen-specific tolerance, carefully taking into account the different phases of stroke, can be used in experimental stroke to lessen ischemic damage. The deep analyses of immunologic mechanisms after stroke are still ongoing, but we hope that their modulation could benefit in the future a large proportion of stroke patients.