Identification of a novel subset of human circulating memory CD4(+) T cells that produce both IL-17A and IL-4.
BACKGROUND
IL-17A has been suggested to play a pathogenic role in bronchial asthma and other allergic disorders.


OBJECTIVE
Study of the relationship between human IL-17A-producing CD4(+) T(H) cells (T(H)17) and IL-4-producing CD4(+) T(H) (T(H)2) cells.


METHODS
T-cell clones generated from the CCR6(+)CD161(+) fraction of human circulating CD4(+) T cells, which contains virtually all T(H)17 cells, as well as circulating CD4(+) T cells from both healthy subjects and patients with asthma, were assessed by flow cytometry for their cytokine production profile.


RESULTS
A small proportion of CCR6(+)CD161(+)CD4(+) T-cell clones showed the ability to produce both IL-17A and IL-4 (T(H)17/T(H)2). T(H)17/T(H)2 clones also produced IL-5, IL-8, IL-9, IL-13, IL-21, and IL-22 and displayed the ability to induce the in vitro secretion of IgE. A very few T(H)17/T(H)2 cells were found among circulating CD4(+) T cells from normal subjects, but their proportions were significantly increased in the circulation of patients with chronic asthma. T(H)17/T(H)2 cells could not be derived from naive umbilical cord blood CD4(+) T cells under any experimental condition. However, when circulating memory CCR6(+)CD161(+)CD4(+) T cells were cloned under appropriate polarizing conditions, T(H)17/T(H)2 clones originated in the presence of IL-4, suggesting that an IL-4-rich microenvironment may induce the shifting of memory T(H)17 cells into T(H)17/T(H)2 cells.


CONCLUSIONS
Because of its peculiar functional properties and the increased numbers in the circulation of patients with bronchial asthma, this previously unknown population of T(H)17/T(H)2 cells may play some role in the pathogenesis of this disease.
Cosmi
Lorenzo
L
Centre of Excellence DENOthe, University of Florence, Florence, Italy.
Maggi
Laura
L
Santarlasci
Veronica
V
Capone
Manuela
M
Cardilicchia
Elisa
E
Frosali
Francesca
F
Querci
Valentina
V
Angeli
Roberta
R
Matucci
Andrea
A
Fambrini
Massimiliano
M
Liotta
Francesco
F
Parronchi
Paola
P
Maggi
Enrico
E
Romagnani
Sergio
S
Annunziato
Francesco
F
D001249:Asthma / Q000276:immunology / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000276:immunology; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D054399:Receptors, CCR6 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
C106311:CCR6 protein, human; D016207:Cytokines; C508717:IL17A protein, human; D020381:Interleukin-17; C527203:KLRB1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D054399:Receptors, CCR6; D015847:Interleukin-4