Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on 4 integrin
Bibliographic record
Abstract
Clonally expanded CD8(+) T lymphocytes are present in multiple sclerosis lesions, as well as in the cerebrospinal fluid of patients with multiple sclerosis. In experimental autoimmune encephalomyelitis, CD8(+) T lymphocytes are found in spinal cord and brainstem lesions. However, the exact phenotype of central nervous system-infiltrating CD8(+) T lymphocytes and the mechanism by which these cells cross the blood-brain barrier remain largely unknown. Using cerebrospinal fluid from patients with multiple sclerosis, spinal cord from experimental autoimmune encephalomyelitis and coronavirus-induced encephalitis, we demonstrate that central nervous system-infiltrating CD8(+) T lymphocytes are mostly of the effector memory phenotype (CD62L(-) CCR7(-) granzymeB(hi)). We further show that purified human effector memory CD8(+) T lymphocytes transmigrate more readily across blood-brain barrier-endothelial cells than non-effector memory CD8(+) T lymphocytes, and that blood-brain barrier endothelium promotes the selective recruitment of effector memory CD8(+) T lymphocytes. Furthermore, we provide evidence for the recruitment of interferon-γ- and interleukin-17-secreting CD8(+) T lymphocytes by human and mouse blood-brain barrier endothelium. Finally, we show that in vitro migration of CD8(+) T lymphocytes across blood-brain barrier-endothelial cells is dependent on α4 integrin, but independent of intercellular adhesion molecule-1/leucocyte function-associated antigen-1, activated leucocyte cell adhesion molecule/CD6 and the chemokine monocyte chemotactic protein-1/CCL2. We also demonstrate that in vivo neutralization of very late antigen-4 restricts central nervous system infiltration of CD8(+) T lymphocytes in active immunization and adoptive transfer experimental autoimmune encephalomyelitis, and in coronavirus-induced encephalitis. Our study thus demonstrates an active role of the blood-brain barrier in the recruitment of effector memory CD8(+) T lymphocytes to the CNS compartment and defines α4 integrin as a major contributor of CD8(+) T lymphocyte entry into the brain.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".