Can changing exposure order make immune-cell families targeting unfamiliar threats persist or disappear despite identical total exposures and resources?

Exposure order determines whether newly activated unfamiliar-specificity CD8 cells acquire familiar peptide–MHC complexes from antigen-presenting cells while recall cytotoxic cells are active. These acquired complexes make unfamiliar cells targets for recall-mediated killing despite their unrelated endogenous specificity. The dominant exclusion mechanism is therefore selective predation on falsely labelled lymphocytes, rather than competition for maintenance capacity. Familiar-first exposure establishes killers before unfamiliar founders acquire the misleading labels; unfamiliar-first exposure can allow the vulnerable acquisition interval to end before recall killing peaks. Preventing this targeting error would stabilize SPV_7 while retaining established recall protection.

Selectively blocking recognition of the acquired familiar complex on unfamiliar cells will restore their post-contraction persistence and target-specific killing without increasing maintenance support. The effect should remain when unfamiliar TCRs show no cross-reactivity to familiar peptides. Absence of acquired-complex-dependent killing, together with successful rescue through another rival's intervention, would reject this explanation.

Increasing nutrients or preventing recall-cell cytotoxicity will not abolish that deficit. Presentation of the antagonist on standardized APCs should reproduce the effect without recall lymphocytes. Failure of independently mapped antagonist regions to predict held-out susceptible TCRs would reject the geometric model.

Exposure order can cause chance loss of unfamiliar immune cells despite favorable average growth predicts instead: Across many replicate cultures with the same unfamiliar TCR, antigen sequence and environmental schedule, persistence will vary probabilistically despite a positive mean invasion exponent. Increasing the initial number of otherwise identical unfamiliar founders will sharply reduce complete loss while leaving measured per-capita growth rates, recall abundance and antigen recognition unchanged. Under an independently acting branching approximation, P_loss(n,T) = q(T)^n, where n is initial founder number and q(T) is one founder's probability of leaving no viable descendants at endpoint T. A nearly deterministic receptor-specific loss that remains after founder-number increases would favor the antagonism or targeted-killing rivals.

Exposure order changes which unfamiliar TCRs encounter antagonistic familiar peptide–MHC ligands during their founding activation window. Familiar peptides can productively stimulate recall receptors while delivering nonproductive or inhibitory signals through different, unfamiliar receptors. Residual familiar presentation therefore creates receptor-specific exclusion regions in antigen-recognition space. Unfamiliar-first exposure permits productive commitment before antagonists appear; familiar-first exposure prevents some founders from completing activation and establishing durable descendants. The apparent population invasion threshold is consequently a recognition-discrimination boundary rather than a shared-capacity boundary. Reducing antagonist overlap would stabilize SPV_7.

Increasing nutrients or preventing recall-cell cytotoxicity will not abolish that deficit. Presentation of the antagonist on standardized APCs should reproduce the effect without recall lymphocytes. Failure of independently mapped antagonist regions to predict held-out susceptible TCRs would reject the geometric model.

Selectively blocking recognition of the acquired familiar complex on unfamiliar cells will restore their post-contraction persistence and target-specific killing without increasing maintenance support. The effect should remain when unfamiliar TCRs show no cross-reactivity to familiar peptides. Absence of acquired-complex-dependent killing, together with successful rescue through another rival's intervention, would reject this explanation.

Exposure order can cause chance loss of unfamiliar immune cells despite favorable average growth predicts instead: Across many replicate cultures with the same unfamiliar TCR, antigen sequence and environmental schedule, persistence will vary probabilistically despite a positive mean invasion exponent. Increasing the initial number of otherwise identical unfamiliar founders will sharply reduce complete loss while leaving measured per-capita growth rates, recall abundance and antigen recognition unchanged. Under an independently acting branching approximation, P_loss(n,T) = q(T)^n, where n is initial founder number and q(T) is one founder's probability of leaving no viable descendants at endpoint T. A nearly deterministic receptor-specific loss that remains after founder-number increases would favor the antagonism or targeted-killing rivals.

Exposure order changes the variance and timing of unfamiliar-founder birth and death events enough to cause demographic extinction even when the independently estimated mean invasion exponent remains positive. Unfamiliar founders encounter their highest death hazard before generating multiple independently surviving descendants in the unfavorable sequence. Once the last founder dies, later favorable maintenance conditions cannot recover that specificity within the experimental renewal interval. The persistent deficit is stored as an absorbing extinction event, not as dominant recall occupancy or a stable dysfunctional cell state. Preventing the early extinction bottleneck would stabilize SPV_7.

Increasing the initial number of otherwise identical unfamiliar founders will sharply reduce complete loss while leaving measured per-capita growth rates, recall abundance and antigen recognition unchanged. Under an independently acting branching approximation, P_loss(n,T) = q(T)^n, where n is initial founder number and q(T) is one founder's probability of leaving no viable descendants at endpoint T. A nearly deterministic receptor-specific loss that remains after founder-number increases would favor the antagonism or targeted-killing rivals.

Selectively blocking recognition of the acquired familiar complex on unfamiliar cells will restore their post-contraction persistence and target-specific killing without increasing maintenance support. The effect should remain when unfamiliar TCRs show no cross-reactivity to familiar peptides. Absence of acquired-complex-dependent killing, together with successful rescue through another rival's intervention, would reject this explanation.

Exposure order blocks unfamiliar immune cells through receptor-specific inhibitory signals predicts instead: With unfamiliar agonist presentation, costimulation and cytokines clamped, familiar peptide variants that retain equivalent recall stimulation but move outside the unfamiliar TCR's independently mapped antagonist region will abolish the order-dependent persistence deficit. Increasing nutrients or preventing recall-cell cytotoxicity will not abolish that deficit. Presentation of the antagonist on standardized APCs should reproduce the effect without recall lymphocytes. Failure of independently mapped antagonist regions to predict held-out susceptible TCRs would reject the geometric model.