Graduate student University of Utah, United States
Disclosure(s):
Annelaure Desmaret, MA: No financial relationships to disclose
Introduction/Rationale: 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.
