Quantitative Analysis of the Role of Receptor Recycling in T Cell Polarization

Arkhipov, Sergey N.; Maly, Ivan V.

doi:10.1529/biophysj.106.083204

Cited by 17 publications

(43 citation statements)

References 33 publications

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“…S8). The KPL-IFF model may implicitly be capturing TCR surface dynamics because directed movement (47) combined with polarized recycling (48,49) of TCR into the immune synapse may balance with TCR internalization (46) to maintain the relatively constant TCR concentration at the immune synapse assumed by the KPL-IFF model, which is consistent with previous calculations (50). A recent study has shown that changing the pMHC affinity can induce a program that over a timescale of several days changes TCR levels (51).…”

Section: Fig 4 Systematic Analyses Of Signaling Models Reveals Thatsupporting

confidence: 82%

“…Fluorescence measurements were performed with the Odyssey Imaging system (LI-COR). A Hill function was fit to the fluorescence over the initial pMHC concentration (in micrograms per milliliter) to determine the EC 50 for each pMHC using Prism. The pMHC concentrations in the functional assays were modified to reflect differences in the immobilization EC 50 as follows: log[pMHC] corrected = log [pMHC] + (log(EC index 50 ) − log(EC 50 )) where the 9V pMHC ligand served as the index.…”

Section: Methodsmentioning

confidence: 99%

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Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Lever

Lim

Krüger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

141

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T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

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Section: Fig 4 Systematic Analyses Of Signaling Models Reveals Thatsupporting

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Lever

Lim

Krüger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

141

View full text Add to dashboard Cite

show abstract

“…Numerical models of recycling explained TCR partitioning between the PM and the intracellular pool [4]. More recently, a model of recycling also addressed the polarized TCR accumulation on the TC-APC interface [5]. However, the interface area in this model was a fixed compartment.…”

Section: Introductionmentioning

confidence: 99%

A Model for the Interplay of Receptor Recycling and Receptor-Mediated Contact in T Cells

Arkhipov

Maly

2007

PLoS ONE

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Orientation of organelles inside T cells (TC) toward antigen-presenting cells (APC) ensures that the immune response is properly directed, but the orientation mechanisms remain largely unknown. Structural dynamics of TC are coupled to dynamics of T-cell receptor (TCR), which recognizes antigen on the APC surface. Engagement of the TCR triggers its internalization followed by delayed polarized recycling to the plasma membrane through the submembrane recycling compartment (RC), which organelle shares intracellular location with the TC effector apparatus. TCR engagement also triggers TC-APC interface expansion enabling further receptor engagement. To analyze the interplay of the cell-cell contact and receptor dynamics, we constructed a new numerical model. The new model displays the experimentally observed selective stabilization of the contact initiated next to the RC, and only transient formation of contact diametrically opposed to the RC. In the general case wherein the TC-APC contact is initiated in an arbitrary orientation to the RC, the modeling predicts that the contact dynamics and receptor recycling can interact, resulting effectively in migration of the contact to the TC surface domain adjacent to the submembrane RC. Using three-dimensional live-cell confocal microscopy, we obtain data consistent with this unexpected behavior. We conclude that a TC can stabilize its contact with an APC by aligning it with the polarized intracellular traffic of TCR. The results also suggest that the orientation of TC organelles, such as the RC and the effector apparatus, toward the APC can be achieved without any intracellular translocation of the organelles.

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“…Furthermore, submembranous flow of the actomyosin cortex contributes to molecular concentration in the IS (10,11). Recent data indicate that polarized exocytosis from a rapid recycling pathway is particularly important for the enrichment of some synapse components, including TCR (12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Rab35 and Its GAP EPI64C in T Cells Regulate Receptor Recycling and Immunological Synapse Formation

Patiño-López¹,

Dong²,

Ben-Aissa³

et al. 2008

Journal of Biological Chemistry

132

173

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Upon antigen recognition, T-cell receptor (TCR/CD3) and other signaling molecules become enriched in a specialized contact site between the T cell and antigen-presenting cell, i.e. the immunological synapse (IS). Enrichment occurs via mechanisms that include polarized secretion from recycling endosomes, but the Rabs and RabGAPs that regulate this are unknown. EPI64C (TBC1D10C) is an uncharacterized candidate RabGAP we identified by mass spectrometry as abundant in human peripheral blood T cells that is preferentially expressed in hematopoietic cells. EPI64C is a Rab35-GAP based both on in vitro Rab35-specific GAP activity and findings in transfection assays. EPI64C and Rab35 dominant negative (DN) constructs each impaired transferrin export from a recycling pathway in Jurkat T-cells and induced large vacuoles marked by transferrin receptor, TCR, and SNAREs implicated in TCR-polarized secretion. Rab35 localized to the plasma membrane and to intracellular vesicles where it substantially colocalized with TfR and with TCR. Rab35 was strongly recruited to the IS. Conjugate formation was impaired by transfection with Rab35-DN or EPI64C and by EPI64C knock down. TCR enrichment at the IS was impaired by Rab35-DN. Thus, EPI64C and Rab35 regulate a recycling pathway in T cells and contribute to IS formation, most likely by participating in TCR transport to the IS. The immunological synapse (IS)3 is a specialized contact between T lymphocytes and antigen-presenting cells (APC) into which accumulate T-cell antigen receptor (TCR), coreceptors, and signaling and cytoskeletal components (1-7). Enrichment of proteins in the IS occurs in part by diffusion and retention at the contact region (i.e."mutual co-capping") (8, 9). Furthermore, submembranous flow of the actomyosin cortex contributes to molecular concentration in the IS (10, 11). Recent data indicate that polarized exocytosis from a rapid recycling pathway is particularly important for the enrichment of some synapse components, including TCR (12-16).Rab proteins are major intracellular transport regulators in eukaryotes; they function in vesicle formation, motility, docking, and fusion (17, 18). Over 60 mammalian Rab proteins have been identified, and each is thought to regulate distinct intracellular transport steps through its temporal and spatial association with various interacting proteins. Guanine exchange factors and GTPase-activating proteins (GAPs) control the switch between active GTP-bound and inactive GDP-bound Rab proteins. Although the TBC (Tre/Bub2/Cdc16) domain is a hallmark of RabGAPs (19), few of the more than 50 putative TBC domain-containing proteins present in the human genome have been paired with their target Rab. One recent notable success was identification of EPI64 (EBP50-PDZ interactor of 64kD) as a GAP specific for Rab27a (20).EPI64 is a broadly expressed TBC domain-containing protein first identified in placental microvilli (21). Recent studies have implicated it in regulating microvillus architecture (22). EPI64 has two paralogs in mouse and...

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Quantitative Analysis of the Role of Receptor Recycling in T Cell Polarization

Cited by 17 publications

References 33 publications

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

A Model for the Interplay of Receptor Recycling and Receptor-Mediated Contact in T Cells

Rab35 and Its GAP EPI64C in T Cells Regulate Receptor Recycling and Immunological Synapse Formation

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