Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22.
The natural history of B-chronic lymphocytic leukemia (CLL) is not entirely explained by intrinsic defects of the neoplastic cell, but is also favored by microenvironmental signals. As CLL cells retain the capacity to respond to CD40 ligand (CD40L) and as CD4(+) T cells are always present in involved tissues, we asked whether malignant CLL cells might produce T cell-attracting chemokines. We studied the chemokine expression of CD19(+)/CD5(+) malignant B cells from peripheral blood (PB), lymph nodes (LN) or bone marrow (BM) of 32 patients and found a major difference. LN- and BM-, but not PB-derived cells, expressed a readily detectable reverse transcription-PCR band for CCL22 and one for CCL17 of variable intensity. CD40 ligation of PB cells induced the mRNA expression of both CCL22 and CCL17. CCL22 was also released in the culture supernatants. These supernatants induced the migration of activated CD4(+), CD40L(+) T cells expressing the CCL22 receptor, CCR4. T cell migration was abrogated by anti-CCL22 antibodies. Immunohistochemistry and cytofluorography studies revealed that a proportion of CD4(+) T cells in CLL LN and BM expressed CD40L. Our data demonstrate that malignant CLL cells chemo-attract CD4(+) T cells that in turn induce a strong chemokine production by the leukemic clone, suggesting a vicious circle, leading to the progressive accumulation of the neoplastic cells.
Ghia
Paolo
P
Department of Oncological Sciences, University of Torino, University Division of Clinical Immunology and Hematology, Ospedale Mauriziano Umberto I, Torino, Italy.
Strola
Giuliana
G
Granziero
Luisa
L
Geuna
Massimo
M
Guida
Giuseppe
G
Sallusto
Federica
F
Ruffing
Nancy
N
Montagna
Licia
L
Piccoli
Paola
P
Chilosi
Marco
M
Caligaris-Cappio
Federico
F
D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D023201:CD40 Ligand / Q000378:metabolism; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003432:Cross-Linking Reagents; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000378:metabolism
C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515354:CCR4 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC; D003432:Cross-Linking Reagents; D012333:RNA, Messenger; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D023201:CD40 Ligand