Mechanisms determining a differential threshold for sensing Src family kinase activity by B and T cell antigen
Simon Borna1, Matej Fabisik1, Kristyna Ilievova1
1Laboratory of Leukocyte Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic.
Abstract:
Although signal transduction by immunoreceptors such as the T cell antigen receptor (TCR), B cell antigen receptor (BCR), and Fc receptors uses the same schematic and similar molecules, the threshold and the fine-tuning are set differently for each receptor. One manifestation of these differences is that inhibition of Src family kinases (SFK) blocks TCR but not BCR signaling. SFKs are key kinases phosphorylating immunoreceptor tyrosine-based activation motifs (ITAM) in both these receptors. However, it has been proposed that in B cells, downstream kinase SYK can phosphorylate ITAM sequences independently of SFK, allowing it to compensate for the loss of SFK activity, whereas its T cell paralog ZAP-70 is not capable of this compensation. To test this proposal, we examined signaling in SYK- and ZAP-70-deficient B and T cell lines expressing SYK or ZAP-70. We also analyzed signal transduction in T cells expressing BCR or B cells expressing part of the TCR complex. We show that when compared with ZAP-70, SYK lowered the threshold for SFK activity necessary to initiate antigen receptor signaling in both T and B cells. However, neither SYK nor ZAP-70 were able to initiate signaling independently of SFK. We further found that additional important factors are involved in setting this threshold. These include differences between the antigen receptor complexes themselves and the spatial separation of the key transmembrane adaptor protein LAT from the TCR. Thus, immunoreceptor sensing of SFK activity is a complex process regulated at multiple levels.
Insights
Src family kinases (SFK) are crucial for T cell antigen receptor (TCR) and B cell antigen receptor (BCR) signaling. While SYK kinase can lower the signaling threshold in B cells, neither SYK nor ZAP-70 can initiate signaling independently of SFK.
Area of Science:
- Immunology
- Cell Signaling
- Molecular Biology
Background:
- Immunoreceptors like TCR and BCR share signaling pathways but differ in activation thresholds.
- Src family kinases (SFKs) are essential for phosphorylating ITAM motifs in these receptors.
- A proposed mechanism for BCR signaling involves SYK compensating for SFK activity, unlike ZAP-70 in T cells.
Purpose of the Study:
- To investigate the proposed compensatory role of SYK in B cell signaling compared to ZAP-70 in T cells.
- To determine if SYK or ZAP-70 can initiate antigen receptor signaling independently of SFKs.
- To identify other factors influencing the threshold for immunoreceptor signaling.
Main Methods:
- Utilized SYK- and ZAP-70-deficient B and T cell lines reconstituted with SYK or ZAP-70.
- Analyzed signal transduction in T cells expressing BCR and B cells expressing TCR components.
- Investigated the role of LAT localization in TCR signaling.
Main Results:
- SYK, compared to ZAP-70, lowered the threshold for SFK activity required for antigen receptor signaling in both T and B cells.
- Neither SYK nor ZAP-70 could initiate signaling independently of SFK activity.
- Differences in antigen receptor complexes and LAT spatial separation from TCR significantly impact signaling thresholds.
Conclusions:
- SYK's ability to lower the signaling threshold is distinct from ZAP-70, but neither can bypass the requirement for SFK activity.
- Multiple factors, including receptor complex composition and LAT localization, contribute to regulating immunoreceptor signaling thresholds.
- SFK activity sensing by immunoreceptors is a complex, multi-level regulated process.
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