Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells
Wendy K. Roberts, … , Jerome B. Posner, Robert B. Darnell
Wendy K. Roberts, … , Jerome B. Posner, Robert B. Darnell
Published June 8, 2009
Citation Information: J Clin Invest. 2009;119(7):2042-2051. https://doi.org/10.1172/JCI36131.
View: Text | PDF
Research Article Oncology

Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells

  • Text
  • PDF
Abstract

Paraneoplastic neurologic disorders (PNDs) offer an uncommon opportunity to study human tumor immunity and autoimmunity. In small cell lung cancer (SCLC), expression of the HuD neuronal antigen is thought to lead to immune recognition, suppression of tumor growth, and, in a subset of patients, triggering of the Hu paraneoplastic neurologic syndrome. Antigen-specific CTLs believed to contribute to disease pathophysiology were described 10 years ago in paraneoplastic cerebellar degeneration. Despite parallel efforts, similar cells have not been defined in Hu patients. Here, we have identified HuD-specific T cells in Hu patients and provided an explanation for why their detection has been elusive. Different Hu patients harbored 1 of 2 kinds of HuD-specific CD8+ T cells: classical IFN-γ–producing CTLs or unusual T cells that produced type 2 cytokines, most prominently IL-13 and IL-5, and lacked cytolytic activity. Further, we found evidence that SCLC tumor cells produced type 2 cytokines and that these cytokines trigger naive CD8+ T cells to adopt the atypical type 2 phenotype. These observations demonstrate the presence of an unusual noncytotoxic CD8+ T cell in patients with the Hu paraneoplastic syndrome and suggest that SCLC may evade tumor immune surveillance by skewing tumor antigen–specific T cells to this unusual noncytolytic phenotype.

Authors

Wendy K. Roberts, Ilana J. Deluca, Ashby Thomas, John Fak, Travis Williams, Noreen Buckley, Athanasios G. Dousmanis, Jerome B. Posner, Robert B. Darnell

×

Figure 2

Identification of the Hu157 epitope and Hu157-specific T cells in patients.

Options: View larger image (or click on image) Download as PowerPoint
Identification of the Hu157 epitope and Hu157-specific T cells in patien...
(A) Screening of Hu peptides in HLA-A0201 transgenic mice. CD8+ T cells purified from AAD mouse spleen cultures were cultured with stimulator cells pulsed with cognate or irrelevant peptide. A positive response was considered at least a 2-fold increase in signal over an irrelevant A0201 binding control peptide. (B) CD8+ T cells were tested for their ability to recognize whole HuD protein processed and presented by primary HHD kidney cells. Wild-type kidney cells were not recognized (data not shown). Peptide 315 was positive in the first screen (A) but was not processed on HLA-A0201 in the kidney cell experiment (B), indicating possible in vitro priming of T cells to this epitope or a low-affinity T cell response, and was not selected for further experiments with patient T cells. (C) Tetramer staining of patient 2, a normal donor, and patient 3 peripheral blood T cells after 1 round of in vitro expansion with HuD157 peptide. Positive control expansions and tetramer staining were with either M1 or CMV, depending on the response of the donor to these viruses. FSC, forward scatter; ND, not determined. (D) Tetramer staining for Hu157 T cells in CSF of Hu patient 2. The percentages of tetramer-positive cells are noted above the boxed populations in C and D. Error bars represent SD of the mean of triplicate wells (A and B).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts