Dataset Information

DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8⁺ T Cell Compartment by Negatively Regulating Tonic TCR Triggering.

ABSTRACT: The control of cytoskeletal dynamics by dedicator of cytokinesis 2 (DOCK2), a hematopoietic cell-specific actin effector protein, has been implicated in TCR signaling and T cell migration. Biallelic mutations in Dock2 have been identified in patients with a recessive form of combined immunodeficiency with defects in T, B, and NK cell activation. Surprisingly, we show in this study that certain immune functions of CD8⁺ T cells are enhanced in the absence of DOCK2. Dock2-deficient mice have a pronounced expansion of their memory T cell compartment. Bone marrow chimera and adoptive transfer studies indicate that these memory T cells develop in a cell-intrinsic manner following thymic egress. Transcriptional profiling, TCR repertoire analyses, and cell surface marker expression indicate that Dock2-deficient naive CD8⁺ T cells directly convert into virtual memory cells without clonal effector T cell expansion. This direct conversion to memory is associated with a selective increase in TCR sensitivity to self-peptide MHC in vivo and an enhanced response to weak agonist peptides ex vivo. In contrast, the response to strong agonist peptides remains unaltered in Dock2-deficient T cells. Collectively, these findings suggest that the regulation of the actin dynamics by DOCK2 enhances the threshold for entry into the virtual memory compartment by negatively regulating tonic TCR triggering in response to weak agonists.

SUBMITTER: Mahajan VS

PROVIDER: S-EPMC6920543 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8+ T Cell Compartment by Negatively Regulating Tonic TCR Triggering.

Mahajan Vinay S VS Demissie Ezana E Alsufyani Faisal F Kumari Sudha S Yuen Grace J GJ Viswanadham Vinayak V Huang Andrew A Tran Johnson Q JQ Moon James J JJ Moon James J JJ Irvine Darrell J DJ Pillai Shiv S

Journal of immunology (Baltimore, Md. : 1950) 20191118 1

The control of cytoskeletal dynamics by dedicator of cytokinesis 2 (DOCK2), a hematopoietic cell-specific actin effector protein, has been implicated in TCR signaling and T cell migration. Biallelic mutations in Dock2 have been identified in patients with a recessive form of combined immunodeficiency with defects in T, B, and NK cell activation. Surprisingly, we show in this study that certain immune functions of CD8+ T cells are enhanced in the absence of DOCK2. Dock2-d ...[more]

PMID: 31740487

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Project description:RationaleThere are growing concerns over the occurrence of adverse physiologic events (PEs) occurring in pilots during operation of United States Air Force and Navy high-performance aircraft. We hypothesize that a heightened inspiratory work of breathing experienced by jet pilots by virtue of the on-board life support system may constitute a "distraction stimulus" consequent to an increased sensation of respiratory muscle effort. As such, the purpose of this study was to determine whether increasing inspiratory muscle effort adversely impacts on attentional performance.MethodsTwelve, healthy participants (age: 29 ± 6 years) were recruited for this study. Participants completed six repetitions of a modified Masked Conjunctive Continuous Performance Task (MCCPT) protocol while breathing against four different inspiratory threshold loads to assess median reaction times (RTs). A computer-controlled threshold loading device was used to set the inspiratory threshold loads. Repeated measures analysis of variances (ANOVAs) were performed to examine: (i) the efficacy of the threshold loading device to impose significantly higher loading at each loading condition; (ii) the effects of loading condition on respiratory muscle effort sensation; and (iii) the influence of hypercapnia on MCCPT scores during inspiratory threshold loading. Generalized additive mixed effects models (GAMMs) were used to examine the potential non-linear effects of respiratory muscular effort sensation, device loading, and hypercapnia, on MCCPT scores during inspiratory threshold loading.ResultsInspiratory threshold loading significantly augmented (P < 0.05) inspiratory effort sensation and the inspiratory pressure-time product (PTP). Our analyses also revealed that median hit RT was positively associated with inspiratory effort sensation during inspiratory loading trials.ConclusionThe findings of this work suggest that it was not increasing inspiratory muscle effort (i.e., PTP) per se, but rather participant's subjective perception of inspiratory "load" that impacts negatively on attentional performance; i.e., as the degree of inspiratory effort sensation increased, sotoo did median hit RT. As such, it is reasonable to suggest that minimizing inspiratory effort sensation (independent of the mechanical output of the inspiratory muscles) during high-performance flight operations may prove useful in reducing pilot RTs during complex behavioral tasks.

Dataset Information

DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8⁺ T Cell Compartment by Negatively Regulating Tonic TCR Triggering.

Publications

DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8<sup>+</sup> T Cell Compartment by Negatively Regulating Tonic TCR Triggering.

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