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The efficiency of CD4 recruitment to ligand-engaged TCR controls the agonist/partial agonist properties of peptide-MHC molecule ligands.
One hypothesis seeking to explain the signaling and biological properties of T cell receptor for antigen (TCR) partial agonists and antagonists is the coreceptor density/kinetic model, which proposes that the pharmacologic behavior of a TCR ligand is largely determined by the relative rates of (a) dissociation ofligand from an engaged TCR and (b) recruitment oflck-linked coreceptors to this ligand-engaged receptor. Using several approaches to prevent or reduce the association of CD4 with occupied TCR, we demonstrate that consistent with this hypothesis, the biological and biochemical consequence of limiting this interaction is to convert typical agonists into partial agonist stimuli. Thus, adding anti-CD4 antibody to T cells recognizing a wild-type peptide-MHC class II ligand leads to disproportionate inhibition of interleukin-2 (IL-2) relative to IL-3 production, the same pattern seen using a TCR partial agonist/antagonist. In addition, T cells exposed to wild-type ligand in the presence of anti-CD4 antibodies show a pattern of TCR signaling resembling that seen using partial agonists, with predominant accumulation of the p21 tyrosine-phosphorylated form of TCR-zeta, reduced tyrosine phosphorylation of CD3epsilon, and no detectable phosphorylation of ZAP-70. Similar results are obtained when the wild-type ligand is presented by mutant class II MHC molecules unable to bind CD4. Likewise, antibody coligation of CD3 and CD4 results in an agonist-like phosphorylation pattern, whereas bivalent engagement of CD3 alone gives a partial agonist-like pattern. Finally, in accord with data showing that partial agonists often induce T cell anergy, CD4 blockade during antigen exposure renders cloned T cells unable to produce IL-2 upon restimulation. These results demonstrate that the biochemical and functional responses to variant TCR ligands with partial agonist properties can be largely reproduced by inhibiting recruitment of CD4 to a TCR binding a wild-type ligand, consistent with the idea that the relative rates of TCR-ligand disengagement and of association of engaged TCR with CD4 may play a key role in determining the pharmacologic properties of peptide-MHC molecule ligands. Beyond this insight into signaling through the TCR, these results have implications for models of thymocyte selection and the use of anti-coreceptor antibodies in vivo for the establishment ofimmunological tolerance
Financing Georgia's Future
This report explores how Georgia finances its expenditures through various revenue sources and compares Georgia's taxes across states and over time on multiple dimensions
Financing an Increased State Role in Funding K-12 Education: An Analysis of Issues and Options
This report presents an analysis of replacing school property tax with alternative state revenue sources. FRC Report 11
Financing Georgia's Future II
This second release of a biennial report focuses on Georgia's taxes, making cross-state comparisons of their structure and exploring revenue performance over time. FRC Report 14
Are Labour Markets Necessarily Local? Spatiality, Segmentation and Scale
This paper draws on recent debates about scale to approach the geography of labour markets from a dynamic perspective sensitive to the spatiality and scale of labour market
restructuring. Its exploration of labour market reconfigurations after the collapse of a major firm (Ansett Airlines) raises questions about geography’s faith in the inherently ‘local’ constitution of labour markets. Through an examination of the job reallocation process after redundancy, the paper suggests that multiple labour markets use and articulate scale in different ways. It argues that labour market rescaling processes are enacted at the critical moment of recruitment, where social networks, personal aspirations and employer preferences combine to shape workers’ destinations
An Integrated-Photonics Optical-Frequency Synthesizer
Integrated-photonics microchips now enable a range of advanced
functionalities for high-coherence applications such as data transmission,
highly optimized physical sensors, and harnessing quantum states, but with
cost, efficiency, and portability much beyond tabletop experiments. Through
high-volume semiconductor processing built around advanced materials there
exists an opportunity for integrated devices to impact applications cutting
across disciplines of basic science and technology. Here we show how to
synthesize the absolute frequency of a lightwave signal, using integrated
photonics to implement lasers, system interconnects, and nonlinear frequency
comb generation. The laser frequency output of our synthesizer is programmed by
a microwave clock across 4 THz near 1550 nm with 1 Hz resolution and
traceability to the SI second. This is accomplished with a heterogeneously
integrated III/V-Si tunable laser, which is guided by dual
dissipative-Kerr-soliton frequency combs fabricated on silicon chips. Through
out-of-loop measurements of the phase-coherent, microwave-to-optical link, we
verify that the fractional-frequency instability of the integrated photonics
synthesizer matches the reference-clock instability for a 1
second acquisition, and constrain any synthesis error to while
stepping the synthesizer across the telecommunication C band. Any application
of an optical frequency source would be enabled by the precision optical
synthesis presented here. Building on the ubiquitous capability in the
microwave domain, our results demonstrate a first path to synthesis with
integrated photonics, leveraging low-cost, low-power, and compact features that
will be critical for its widespread use.Comment: 10 pages, 6 figure
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