DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 + T Cell Compartment by Negatively Regulating Tonic TCR Triggering
Name
nihms-1541557.pdf
Description
Accepted version
Size
1.65 MB
Format
Adobe PDF
Checksum (MD5)
06847728b90799079b5a1728a19be7ab
Author(s)
Mahajan, Vinay S
Demissie, Ezana
Alsufyani, Faisal
Kumari, Sudha
Yuen, Grace J
Viswanadham, Vinayak
Huang, Andrew
Tran, Johnson Q
Moon, James J
Irvine, Darrell J
Date Issued
2020
Journal
Journal of immunology
Publisher
The American Association of Immunologists
Version
Author's final manuscript
Abstract
Copyright © 2019 by The American Association of Immunologists, Inc. 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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.4049/JIMMUNOL.1900440
