Constitutive Lck Activity Drives Sensitivity Differences between CD8+ Memory T Cell Subsets.
CD8(+) T cells develop increased sensitivity following Ag experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (TEM) that >50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with <20% in central memory T cells (TCM). Immediately proximal to Lck signaling, we observed enhanced Zap-70 phosphorylation in TEM following TCR ligation compared with TCM Furthermore, we observed superior cytotoxic effector function in TEM compared with TCM, and we provide evidence that this results from a lower probability of TCM reaching threshold signaling owing to the decreased magnitude of TCR-proximal signaling. We provide evidence that the differences in Lck constitutive activity between CD8(+) TCM and TEM are due to differential regulation by SH2 domain-containing phosphatase-1 (Shp-1) and C-terminal Src kinase, and we use modeling of early TCR signaling to reveal the significance of these differences. We show that inhibition of Shp-1 results in increased constitutive Lck activity in TCM to levels similar to TEM, as well as increased cytotoxic effector function in TCM Collectively, this work demonstrates a role for constitutive Lck activity in controlling Ag sensitivity, and it suggests that differential activities of TCR-proximal signaling components may contribute to establishing the divergent effector properties of TCM and TEM. This work also identifies Shp-1 as a potential target to improve the cytotoxic effector functions of TCM for adoptive cell therapy applications.
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016;
Duane
D
Moogk
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016;
Shi
S
Zhong
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Zhiya
0000-0003-3742-5902
Z
Yu
Department of Chemical and Biomolecular Engineering, University of Houston, TX 77004;
Ivan
0000-0003-3830-6569
I
Liadi
George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
William
0000-0003-4268-3148
W
Rittase
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; New York University Medical Scientist Training Program, New York, NY 10016;
Victoria
0000-0001-9376-1279
V
Fang
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016;
Janna
J
Dougherty
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016;
Arianne
A
Perez-Garcia
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; Ronald Perelman Department of Dermatology, New York University School of Medicine, New York, NY 10016;
Iman
I
Osman
George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
Cheng
0000-0002-1718-565X
C
Zhu
Department of Chemical and Biomolecular Engineering, University of Houston, TX 77004;
Navin
0000-0001-7524-8228
N
Varadarajan
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Nicholas P
NP
Restifo
Department of Cell Biology, New York University School of Medicine, New York, NY 10016; and.
Alan B
AB
Frey
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; Department of Pathology, New York University School of Medicine, New York, NY 10016 Michelle.Krogsgaard@nyumc.org.
Michelle
M
Krogsgaard
D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology* / Q000378:metabolism; D008390:Markov Chains; D051379:Mice; D016133:Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D059008:Time-Lapse Imaging
D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)