Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties.
CD8(+) T lymphocytes play a key role in host defense, in particular against important persistent viruses, although the critical functional properties of such cells in tissue are not fully defined. We have previously observed that CD8(+) T cells specific for tissue-localized viruses such as hepatitis C virus express high levels of the C-type lectin CD161. To explore the significance of this, we examined CD8(+)CD161(+) T cells in healthy donors and those with hepatitis C virus and defined a population of CD8(+) T cells with distinct homing and functional properties. These cells express high levels of CD161 and a pattern of molecules consistent with type 17 differentiation, including cytokines (e.g., IL-17, IL-22), transcription factors (e.g., retinoic acid-related orphan receptor gamma-t, P = 6 x 10(-9); RUNX2, P = 0.004), cytokine receptors (e.g., IL-23R, P = 2 x 10(-7); IL-18 receptor, P = 4 x 10(-6)), and chemokine receptors (e.g., CCR6, P = 3 x 10(-8); CXCR6, P = 3 x 10(-7); CCR2, P = 4 x 10(-7)). CD161(+)CD8(+) T cells were markedly enriched in tissue samples and coexpressed IL-17 with high levels of IFN-gamma and/or IL-22. The levels of polyfunctional cells in tissue was most marked in those with mild disease (P = 0.0006). These data define a T cell lineage that is present already in cord blood and represents as many as one in six circulating CD8(+) T cells in normal humans and a substantial fraction of tissue-infiltrating CD8(+) T cells in chronic inflammation. Such cells play a role in the pathogenesis of chronic hepatitis and arthritis and potentially in other infectious and inflammatory diseases of man.
Department of Medicine II and Spemann Graduate School of Biology and Medicine, University of Freiburg, 79106 Freiburg, Germany.
Eva
E
Billerbeck
Yu-Hoi
YH
Kang
Lucy
L
Walker
Helen
H
Lockstone
Stefanie
S
Grafmueller
Vicki
V
Fleming
Jonathan
J
Flint
Chris B
CB
Willberg
Bertram
B
Bengsch
Bianca
B
Seigel
Narayan
N
Ramamurthy
Nicole
N
Zitzmann
Eleanor J
EJ
Barnes
Jonarthan
J
Thevanayagam
Anisha
A
Bhagwanani
Alasdair
A
Leslie
Ye H
YH
Oo
Simon
S
Kollnberger
Paul
P
Bowness
Oliver
O
Drognitz
David H
DH
Adams
Hubert E
HE
Blum
Robert
R
Thimme
Paul
P
Klenerman
D000410:Alanine Transaminase / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D008156:Luciferases; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D016207:Cytokines; C527203:KLRB1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D018121:Receptors, Cytokine; D008156:Luciferases; D000410:Alanine Transaminase