Direct cellular interaction with activated CD4(+) T cells overcomes hyporesponsiveness of B-cell chronic lymphocytic leukemia in vitro.
The proliferative response of clonal B cells from patients with chronic lymphocytic leukemia (B-CLL) is drastically reduced compared to normal B lymphocytes stimulated via the B cell antigen receptor complex or by CD40 ligation. In the present study we demonstrate that hyporesponsiveness of CLL-B cells can be overcome by stimulatory pathways mediated by activated CD4(+) T cells. In contrast to CD40 ligation, costimulation with activated T cells promotes a proliferative response in CLL-B cells identical to that in normal B cells. Furthermore, coculture with activated T cells improved survival of CLL-B cells in vitro. Differentiation of CLL-B cells into IgM producing cells was promoted, as well. However, the capacity for IgM secretion remained impaired compared to that of normal B cells. For T-cell-mediated B cell activation direct cellular contact with activated T helper cells is absolutely required. Prevention of CD40/CD40L interaction by CD40 antibody caused only partial inhibition of B cell activation, suggesting that additional signals are involved in T-B cell interaction. Whereas interruption of the ligand pairs CD11a/CD54, CD5/CD72, CD27/CD70 had no influence, the addition of CD58 antibody completely inhibited B cell activation by activated T cells. In costimulation with cellular signals the presence of B-cell-tropic cytokines, such as IL-2 and IL-4, was required to optimize B-CLL proliferation, as demonstrated by the use of neutralizing antibodies. We conclude from these results that proliferative hyporesponsiveness by CLL-B cells can be circumvented by antigen-nonspecific signals in addition to CD40 which are mediated by direct contact with activated T helper cells.
Third Department of Medicine, The Johannes Gutenberg University School of Medicine, Mainz, Germany.
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T
Tretter
M
M
Schuler
F
F
Schneller
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U
Brass
M
M
Esswein
M J
MJ
Aman
C
C
Huber
C
C
Peschel
D015703:Antigens, CD / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000276:immunology*; D008213:Lymphocyte Activation
D015703:Antigens, CD; D000954:Antigens, Surface; D019013:CD40 Antigens; D007075:Immunoglobulin M; D007376:Interleukin-2