Functional heterogeneity of cytokines and cytolytic effector molecules in human CD8+ T lymphocytes.
CD8(+) T cells use a number of effector mechanisms to protect the host against infection. We have studied human CD8(+) T cells specific for CMV pp65(495-503) epitope, or for staphylococcal enterotoxin B, for the expression patterns of five cytokines and cytolytic effector molecules before and after antigenic stimulation. Ex vivo, the cytolytic molecule granzyme B was detected in a majority of circulating CMV-specific CD8(+) T cells, whereas perforin was rarely expressed. Both were highly expressed after Ag-specific activation accompanied by CD45RO up-regulation. TNF-alpha, IFN gamma, and IL-2 were sequentially acquired on recognition of Ag, but surprisingly, only around half of the CMV-specific CD8(+) T cells responded to antigenic stimuli with production of any cytokine measured. A dominant population coexpressed TNF-alpha and IFN-gamma, and cells expressing TNF-alpha only, IFN-gamma only, or all three cytokines together also occurred at lower but clearly detectable frequencies. Interestingly, perforin expression and production of IFN-gamma and TNF-alpha in CD8(+) T cells responding to staphylococcal enterotoxin B appeared to be largely segregated, and no IL-2 was detected in perforin-positive cells. Together, these data indicate that human CD8(+) T cells can be functionally segregated in vivo and have implications for the understanding of human CD8(+) T cell differentiation and specialization and regulation of effector mechanisms.
Sandberg
J K
JK
Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94141, USA. jsandberg@gladstone.ucsf.edu
Fast
N M
NM
Nixon
D F
DF
D000954:Antigens, Surface / Q000096:biosynthesis; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology; D054353:Perforin; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014763:Viral Matrix Proteins / Q000276:immunology / Q000378:metabolism
D000954:Antigens, Surface; D015415:Biomarkers; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D054353:Perforin; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases