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Abstract
Affinity and dose of T cell receptor (TCR) interaction with antigens govern the magnitude of CD4+ T cell responses, but questions remain regarding the quantitative translation of TCR engagement into downstream signals. We find that while the response of mouse CD4+ T cells to antigenic stimulation is bimodal, activated cells exhibit analog responses proportional to signal strength. Gene expression output reflects TCR signal strength, providing a signature of T cell activation. Expression changes rely on a pre-established enhancer landscape and quantitative acetylation at AP-1 binding sites. Finally, we show that graded expression of activation genes depends on ERK pathway activation, suggesting that an ERK-AP-1 axis plays an important role in translating TCR signal strength into proportional activation of enhancers and genes essential for T cell function.
Highlights
The question of how the T cell receptors (TCRs) of CD4+ T cells respond to ligands of differing affinities and concentrations with such remarkable specificity is of great interest to the study of immunity
Even small differences in the number or affinity of these pMHC-TCR interactions are read by the TCR and have important consequences for the nature and extent CD4+ T cell activation; high-affinity interactions lead to inflammatory responses at a lower concentration of antigen, increased Interleukin 2 (IL2) and IFNg production, and increased proliferation (Heber-Katz et al, 1982; Hedrick et al, 1982; Solinger et al, 1979; Alexander, 1993; Rogers and Peptide dose, 1999; Rogers et al, 1998; Sloan-Lancaster et al, 1993; Tubo et al, 2013), whereas lower affinity interactions can lead to incomplete phosphorylation of downstream signaling complexes
We have shown that the traditional model of a purely digital TCR response is too simple; on a per-cell basis, stronger TCR signals result in higher levels of phosphorylated ERK, a proportional increase in enhancer acetylation, and quantitative increases in activation markers such as CD69 and CD25 (Figure 7F)
Summary
The question of how the T cell receptors (TCRs) of CD4+ T cells respond to ligands of differing affinities and concentrations with such remarkable specificity is of great interest to the study of immunity. Variations in signal efficiency are caused by the generated TCR sequence (Hedrick et al, 1984; Jerne, 1971), genetic differences in MHC (Heber-Katz et al, 1982; Hedrick et al, 1982), and the peptide being presented (Solinger et al, 1979).
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