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Secretion by Circulating CD8 T Lymphocytes: Implications of a Novel Approach for T Cell Monitoring in Infectious and Malignant Diseases1
*
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, and
Multidisciplinary Oncology Center, University Hospital, Lausanne, Switzerland; and
Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
To elucidate the functional heterogeneity of Ag-specific T
lymphocyte populations, we combined labeling of lymphocytes with
MHC/peptide tetramers and a cell surface affinity matrix for IFN-
.
Magnetic cell sorting of IFN--positive lymphocytes allowed the
selective enrichment and identification of live Ag-specific
cytokine-secreting cells by flow cytometry. Naive, memory, and effector
Ag-specific populations were evaluated in healthy HLA-A2 individuals.
Significant fractions of influenza- and CMV-specific cells secreted
IFN- upon challenge with cognate peptide, consistent with an
effector/memory status. The sensitivity of the approach allowed the
detection of significant numbers of CMV-specific IFN--secreting
cells ex vivo (i.e., without Ag stimulation). This was not apparent
when using previously described assays, namely, ELISPOT or
intracellular IFN- staining (cytospot). CD8+ T cells
specific for the melamoma-associated Ag Melan-A/MART-1 did not produce
IFN- upon challenge with cognate peptide, reminiscent with their
naive functional state in healthy individuals. In contrast,
CD45RAlow Melan-A/MART-1 tumor-specific cells from three of
three melanoma patients presented levels of activity similar to those
found for influenza- or CMV virus-specific lymphocytes, compatible with
a functional differentiation into competent effector/memory T
lymphocytes in vivo. Notably, a sizable fraction of
Melan-A/MART-1-specific cells from a patient secreted IFN- ex vivo
following peptide-based vaccination. Thus, the high sensitivity of the
assay provides a valuable tool to monitor effector T cell responses in
different clinical situations.
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