Feedback control of T–cell receptor activation

Abstract

The specificity and sensitivity of T-cell recognition is vital to the immune response. Ligand engagement with the T-cell receptor (TCR) results in the activation of a complex sequence of signalling events, both on the cell membrane and intracellularly. Feedback is an integral part of these signalling pathways, yet is often ignored in standard accounts of T-cell signalling. Here we show, using a mathematical model, that these feedback loops can explain the ability of the TCR to discriminate between ligands with high specificity and sensitivity, as well as provide a mechanism for sustained signalling. The model also explains the recent counter-intuitive observation that endogenous 'null' ligands can significantly enhance T-cell signalling. Finally, the model may provide an archetype for receptor switching based on kinase-phosphatase switches, and thus be of interest to the wider signalling community.

Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital ERK Responses

“…To deal with this problem, some form of filtration or noise suppression is needed, which in signal processing would typically be mediated by a negative-feedback system [41]. Recently, the SH2 domain-containing tyrosine phosphatase (SHP-1) has been shown to play such a role in TCR signaling [27,42], and some models of TCR discrimination have incorporated this feedback to limit responses to high levels of weakly binding ligands [23,43]. However, such negative feedback alone would also act to diminish the sensitivity of the system to otherwise agonist (stimulatory) ligands.…”

Spatial and Temporal Dynamics of T Cell Receptor Signaling with a Photoactivatable Agonist

“…Theoretical studies have described how quickly positive and negative feedback can contribute to ligand discrimination and sensitivity (AltanBonnet and Germain, 2005;Chan et al, 2004;Li et al, 2004), and indeed, the TCR signaling network contains a number of distinct feedback loops (Egen et al, 2002;Naramura et al, 2002;Sanjuan et al, 2001;Stefanova et al, 2003;Wang et al, 2000;Zhong et al, 2002). However, little is known about the timescale over which these interactions occur and whether certain branches of the network are affected more than others.…”

“…Indeed, modest changes in the lifetime of a pMHC-TCR interaction can lead to profound differences in biological responses (Kersh et al, 1998). A number of theoretical models have been proposed that attempt to explain how the TCR signaling network can combine sensitivity, speed, and discriminatory power in this manner (Altan-Bonnet and Germain, 2005;Chan et al, 2001;Chan et al, 2004;McKeithan, 1995).…”

Understanding specificity and sensitivity of T-cell recognition

“…This results in a negative feedback loop because some phosphatases, such as SHP-1, are themselves activated by Lck [37,38]. These feedback pathways suggest a simple model for Lck activation, which assumes that, on TCR engagement, there is an accumulation of Lck local to the TCR over time [35] ( Figure 2). The mechanism by which this accumulation occurs is not explained in the model but might include the spatial reorganisation of lipid rafts enriched in kinases (and/or exclusion of CD45 and other phosphatases).…”

“…These involve multiple positive and negative feedback pathways, which can result in the introduction of delays [35]. Lck is a member of the Src family of kinases, whose activation is proximal to the TCR binding of pMHC.…”