T cells selectively filter oscillatory signals on the minutes timescale

Abstract

T cells experience complex temporal patterns of stimulus via receptor–ligand-binding interactions with surrounding cells. From these temporal patterns, T cells are able to pick out antigenic signals while establishing self-tolerance. Although features such as duration of antigen binding have been examined, our understanding of how T cells interpret signals with different frequencies or temporal stimulation patterns is relatively unexplored. We engineered T cells to respond to light as a stimulus by building an optogenetically controlled chimeric antigen receptor (optoCAR). We discovered that T cells respond to minute-scale oscillations of activation signal by stimulating optoCAR T cells with tunable pulse trains of light. Systematically scanning signal oscillation period from 1 to 150 min revealed that expression of CD69, a T cell activation marker, reached a local minimum at a period of ∼25 min (corresponding to 5 to 15 min pulse widths). A combination of inhibitors and genetic knockouts suggest that this frequency filtering mechanism lies downstream of the Erk signaling branch of the T cell response network and may involve a negative feedback loop that diminishes Erk activity. The timescale of CD69 filtering corresponds with the duration of T cell encounters with self-peptide–presenting APCs observed via intravital imaging in mice, indicating a potential functional role for temporal filtering in vivo. This study illustrates that the T cell signaling machinery is tuned to temporally filter and interpret time-variant input signals in discriminatory ways.

GWAS associated Variants, Non-genetic Factors, and Transient Transcriptome in Multiple Sclerosis Etiopathogenesis: a Colocalization Analysis

“…This confirms the highly contextual role of eRNAs through the control of transcription burst frequencies, which are known to influence cell-type-specific gene expression profiles (Larsson et al, 2019). Along these lines, a recent study showed that T cells selectively filter oscillatory signals within the minute timescale (O’Donoghue et al, 2021), further supporting the aforementioned model.…”

Optophysiology: Illuminating cell physiology with optogenetics

“…Figure 6b) based on either iLID, cpLID (cpLOV2-ssrA and sspB) or CRY2-CIB1 have been developed to conditionally reconstitute a split CAR into a fully functional CAR in the presence of blue light (23,302,303). In the dark, the tumor antigen-sensing unit and/or the effector domains remain separately expressed in two constructs.…”

“…Optogenetics has also been applied to control the activity of therapeutic immune cells, such as the chimeric antigen receptor (CAR) T cells. Optogenetic or light-switchable chimeric antigen receptors (optoCARs or LiCARs; FIGURE 6 B ) based on iLID, cpLID (cpLOV2-ssrA and -sspB), or CRY2-CIB1 have been developed to conditionally reconstitute a split CAR into a fully functional CAR in the presence of blue light ( 23 , 302 , 303 ). In the dark, the tumor antigen-sensing unit and/or the effector domains remain separately expressed in two constructs.…”

Staggered starts in the race to T cell activation

“…systems is inherently limited by the ability to find an altered peptide ligand (APL) that exhibits the desired binding behavior, making questions about specific lengths of pMHC engagement or patterns of binding and rebinding events difficult to answer. To circumvent this issue, several groups have recently developed optogenetic receptor-ligand systems in which binding kinetics are controlled by light patterns [23][24][25][26] (Box 1). While the synthetic nature of optogenetic systems must be considered in interpreting results, these methods enable a new level of precision in dissecting the temporal binding requirements of T cell activation.…”