Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Copyright © 2021 The Authors. 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.

Original publication

DOI

10.1126/scisignal.aay9363

Type

Journal article

Journal

Science Signaling

Publication Date

19/01/2021

Volume

14