Frequency encoding of T cell receptor engagement dynamics in calcium time series

¹ INSERM U563

^* To whom correspondence should be addressed. E-mail: utznycle{at}toulouse.inserm.fr.

Submitted on December 19, 2003
Revised on February 18, 2004
Accepted on 16 September 2004

	Abstract

The sustained increase of the cytosolic calcium concentration ([Ca 2+] i) plays a central role in T cell receptor (TCR) mediated T cell activation. Previous experiments using a [Ca 2+] i clamp technique have demonstrated that specificity is encoded by the [Ca 2+] i oscillation frequency since cytokine transcription factors are activated in a frequency dependent manner. An outstanding question is how encoding of specific activation occurs under physiological conditions. In this case continuous TCR interactions with specific peptides bound to cell surface-associated major histocompatibility complexes (MHC) are driving the sustained [Ca 2+] i increase. Addressing this question we analyzed [Ca 2+] i time series from individual T cells mathematically. We are able to identify signal-fluctuations associated with the TCR triggering dynamics. Also, we find that [Ca 2+] i time series associated with T cells activated to IFN- production exhibit oscillations with higher frequencies than the time series corresponding to T cells not activated to IFN- production. We show that signal autocorrelations are a means in the distinction of functional signals according to their associated cytokine production. The signal level, however, allows for the distinction of non-functional from functional signals. These findings provide strong evidence for specificity encoding of biological functions in intracellular signals via signal level and signal correlations.

Key Words: T cell receptor signaling, bioinformatics/biostatistics, encoding of specificity, stochastic models, sustained cytosolic calcium increase, time series/data analysis

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