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

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.