Low-affinity CD8+ T cells drive cerebral malaria and redefine the afifnity-effector paradigm 2262761

Introduction Cerebral malaria (CM) remains the deadliest form of Plasmodium infection. Its pathology stems from CD8+ T cell-mediated disruption of the blood-brain barrier (BBB). High affinity T cells are classically viewed as dominant effectors in polyclonal immune responses. Methods Our data reveal a striking inversion of this paradigm: low-affinity CD8+ T cells are the main drivers of disease in experimental cerebral malaria (ECM). Using Plasmodium bergei ANKA infections of C57BL/6 mice we show that brain-infiltrating CD8+ T cells during ECM had predominantly low-affinity T cell receptors. The pathogenic capacity of those cells was assessed through adoptive transfers into TCRα-/- recipient mice using 3 different sources of high and low affinity T cells: flow sorted, viral-derived and retrogenic. Results In all cases low-affinity CD8 T cells were pathogenic leading to lethal disruption of the blood brain barrier, whereas high-affinity cells failed to cause disease. Both high and low affinity T cells make interferon-y but high affinity cells upregulate more markers that are typical of exhaustion. Conclusion We hypothesize that the high affinity cells may undergo exhaustion or apoptosis explaining their reduced pathogenic potential. Interestingly, high affinity TCRs formed longer-lived bonds under force than low-affinity ones, suggesting that distinct mechanodynamic properties may underlie the transcriptional control leading to divergent profiles. Our data challenges a core principle of T cell biology and reveals unexpected complexity in TCR affinity-disease relationships.