Production of TARC and MDC by naive T cells in asthmatic patients.
The helper (Th)2 cell-attracting chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) are ligands for the chemokine receptor CCR4. A number of cellular sources of TARC and MDC have been identified, including not only macrophages, dendritic cells, and natural killer cells, but also bronchial epithelial cells. Recent studies report that TARC and MDC may serve as pivotal chemokines for the development of Th2-dominated experimental allergen-induced asthma. This study was designed to assess TARC and MDC production by CD4+ T cells, including naive T cells and memory/effector T cells, purified from peripheral blood mononuclear cells in patients with asthma. Asthmatic subjects included in this study had mild asthmatic symptoms, positive skin test responses to house dust mite allergen, and elevated level of Dermatophagoides farinae immunoglobulin E in the sera. CD4+ T cells--CD45RA+ CD4+ T cells--as naive T cells and CD45RO+ CD4+ T cells--as memory/effector T cells--were purified by negative selection from peripheral blood mononuclear cells obtained from asthmatic patients (n = 6) and healthy controls (n = 6). These cells and established Th1/Th2 cell lines were then cultured in the presence of both anti-CD3 and -CD28 antibodies. After 48 hr of incubation, concentrations of TARC, MDC, interleukin (IL)-4, IL-5, and interferon-gamma in the supernatants were measured by enzyme-linked immunoadsorbent assay. Reverse transcriptase-polymerase chain reaction was performed to analyze mRNA expression of TARC and MDC. Our results clearly showed that TARC and MDC were produced by activated CD45RA+ CD4+ T cells rather than by activated CD45RO+ CD4+ T cells, and the levels of these chemokines in the asthmatic patients were higher than those in the healthy controls. Furthermore, these chemokines production by Th2 cell lines were greater than those by Th1 cell lines, but the level were smaller than those by naive T cells. Our studies suggest that TARC and MDC are produced by naive T cells rather than by memory/effector T cells, including Th2 cells, in asthmatic patients, and these chemokines were produced at modest levels in any T-cell populations from healthy controls. Taken together, naive T cells in asthma have a peculiar function to produce TRAC and MDC, which contribute to local migration of Th2 cells into lung and lymphoid tissues, along with a function as precursor for memory/effector T cell. This novel function of naive T cells may be implicated in the development of asthma.
Hirata
Hirokuni
H
Department of Pulmonary Medicine and Clinical Immunology, Dokkyo University School of Medicine, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.
Arima
Masafumi
M
Cheng
Gang
G
Honda
Kyoko
K
Fukushima
Fumiya
F
Yoshida
Nozomi
N
Eda
Fukiko
F
Fukuda
Takeshi
T
D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001249:Asthma / Q000276:immunology / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics*; D040001:Dermatophagoides farinae / Q000276:immunology; D005260:Female; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C106230:CCL17 protein, human; C515482:CCL22 protein, human; C497964:CD86 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC; D008562:Membrane Glycoproteins; D017493:Leukocyte Common Antigens