Research ArticleImmunology

Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinities is overcome by costimulation

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Science Signaling  19 Jan 2021:
Vol. 14, Issue 666, eaay9363
DOI: 10.1126/scisignal.aay9363

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Adapting to antigens

Cell surface T cell receptors (TCRs) are engaged by antigens, leading to T cell activation and cytokine production. Trendel et al. exposed primary human CD8+ T cells to a wide range of antigens and mathematically analyzed cellular cytokine production to determine both how T cells respond to constant antigen stimulation and the effect of down-regulation of the TCR from the cell surface. The authors showed that T cells adapted to constant antigen stimulation by stopping cytokine production even in the absence of complete TCR down-regulation. Signaling by costimulatory receptors broke this adaptation and maintained cytokine production. These results have implications for the design of chimeric antigen receptors that must maintain cellular activation to provide effective therapies.

Abstract

Maintaining and limiting T cell responses to constant stimulation with antigen are critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) activates signaling that stimulates T cells to produce cytokines and also leads to the down-regulation of cell surface TCRs. In other systems, receptor down-regulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation, which requires complete down-regulation of the receptor or the ligand; however, this is not the case for the TCR. Here, we observed that in vitro–expanded primary human T cells exhibited perfect adaptation with respect to cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR down-regulation. By directly fitting a mechanistic model to these data, we showed that TCR down-regulation produced imperfect adaptation, but, when coupled to a switch, produced perfect adaptation in terms of cytokine production. A prediction of this model was that TCR signaling induced by peptide-bound major histocompatibility complex (pMHC) continues after adaptation, which we confirmed by showing that, whereas costimulation could not prevent adaptation, signaling by the costimulatory receptors CD28 and 4-1BB reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We showed that adaptation also applied to first-generation chimeric antigen receptor (CAR) T cells but was partially avoided with second-generation CARs. These findings highlight that perfect adaptation limits the responses of T cells, rendering them dependent on costimulation for sustained responses.

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