Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege.
Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4(+) cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4(+) T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4(+) T cells and inhibit the migration of CD4(+)CD25(+) T cells in vitro. Recognition of the importance of CCR4(+) Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.
Ishida
Takashi
T
Department of Internal Medicine and Molecular Science and Clinical Pathology, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho-chou, Mizuho-ku, Nagoya-shi, Aichi, Japan. itakashi@med.nagoya-cu.ac.jp
Ishii
Toshihiko
T
Inagaki
Atsushi
A
Yano
Hiroki
H
Komatsu
Hirokazu
H
Iida
Shinsuke
S
Inagaki
Hiroshi
H
Ueda
Ryuzo
R
D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D054414:Chemokine CCL17; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology; D019742:Chemokines, CC / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D006689:Hodgkin Disease / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000911:Antibodies, Monoclonal; C106230:CCL17 protein, human; C515354:CCR4 protein, human; D054414:Chemokine CCL17; D018925:Chemokines; D019742:Chemokines, CC; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D015375:Receptors, Interleukin-2