A sharp T-cell antigen receptor signaling threshold for T-cell proliferation

Abstract

T-cell antigen receptor (TCR) signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR signaling specifically and efficiently. We have also characterized a fluorescent reporter Nur77-eGFP transgenic mouse line in which T cells up-regulate GFP uniquely in response to TCR stimulation. The combination of these technologies unmasked a sharp TCR signaling threshold for commitment to cell division both in vitro and in vivo. Further, we demonstrate that this threshold is independent of both the magnitude of the TCR stimulus and Interleukin 2. Similarly, we identify a temporal threshold of TCR signaling that is required for commitment to proliferation, after which T cells are able to proliferate in a Zap70 kinase-independent manner. Taken together, our studies reveal a sharp threshold for the magnitude and duration of TCR signaling required for commitment of T cells to proliferation. These results have important implications for understanding T-cell responses to infection and optimizing strategies for immunomodulatory drug delivery.

Substrate stiffness regulates B‐cell activation, proliferation, class switch, and T‐cell‐independent antibody responses in vivo

“…Our speculation is that for both B and T cells, their proliferation efficiencies are determined by multisignaling pathway, among which the activation of PI3K-Akt-FoxO1 plays an important role [34,35]. Indeed, this speculation is supported by a recent study in T cells by Weiss and his colleagues that there is a sharp TCR signaling threshold as measured by Zap70 activation (like the Syk activation in B cells) for the commitment to cell division both in vitro and in vivo experiments [40]. Of great importance is that this threshold is a fixed value that is independent of the magnitude of the TCR stimulus.…”

Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine

“…30, 57; a gift from Julie Zikherman, UCSF), and CD45.1 (Jackson) lines that have been maintained on a C57/Bl6 background for more than 10 generations. OT-I/ZAP70AS/CD45.1 and OT-I/ZAP70 +/-/CD45.1 animals were described previously (30,57) and were a gift from Art Weiss (UCSF). IL-15 knockout animals were a gift from Shomyseh Sanjabi (UCSF).…”

Dynamic Tuning of Lymphocytes: Physiological Basis, Mechanisms, and Function

“…In particular, an affinity threshold for activation of the TCR-signaling module would in principle be defined in this model for any fixed set of other relevant parameters as the minimal affinity required for activated ERK to reach a sufficient local concentration, enabling the self-enhancing mechanism to overcome the negative, restoring force of SHP-1, at which point the positive loop ignites. Overcoming the TCR-activation threshold (that is, the local excitation threshold) does not necessarily lead to cell activation, as additional excitation thresholds may arise downstream, where the concentration and activity of excitation molecules reflect the number of activated TCRs and their rate of activation, as well as the amount and quality of signals transduced via other channels (29). In the following, we generally use the terms excitation threshold and activation threshold interchangeably, for simplicity, unless otherwise stated.…”

“…The latter is important, though, for the integration of TCR-generated signals by downstream modules, into which accessory (non-TCR) signals are also channeled. This downstream integration of excitation signals and their negative controls may also be capable of showing bistability and switching (29), although switching can be delayed by hours, during which a competition with induced and preexisting de-excitation factors takes place. An organized network of several signaling modules (21) with threshold-controlled excitation thresholds (35) is envisioned to define, collectively, the T cell activation threshold (or a set of thresholds for the activation of different effector functions).…”