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.

Maintaining and limiting T cell responses to constant antigen stimulation is critical to eliminate pathogens and maintain self-tolerance, respectively. Antigen recognition by the T cell receptor (TCR) induces signalling that can activate T cells to produce cytokines and downregulation of the TCR. Precisely how TCR downregulation controls T cell responses to constant antigen stimulation is controversial. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation but this relies on complete downregulation of the receptor or the ligand, which is not the case for the TCR. Here, we observed that primary human effector T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation. Perfect adaptation was observed across a wide variation in antigen concentration (2,000-fold) and affinity (100,000-fold) even with partial TCR downregulation. A mechanistic model showed that TCR downregulation produces imperfect adaptation, but when coupled to digital signalling led to perfect adaptation in cytokine production. A prediction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings highlight the role of even partial TCR downregulation in generating perfect adaptation with implications for costimulation and adoptive T cell therapies.

Original publication

DOI

10.1101/535385

Type

Journal article

Journal

BioRxiv

Publication Date

30/01/2019