The CD44 variant isoforms CD44v6 and CD44v7 are expressed by distinct leukocyte subpopulations and exert non-overlapping functional activities.
We have described recently that anti-CD44s, anti-CD44v6 and anti-CD44v7 interfere with delayed-type hypersensitivity (DTH) reactions. Yet, TNBS-induced colitis can be cured only by anti-CD44v7. To clarify the mechanisms underlying the divergent functional activities of CD44v6 and CD44v7 we explored their contribution to lymphocyte activation in vivo and in vitro. CD44v6 and CD44v7 are distinctly expressed on subpopulations of activated lymphocytes. Expression of CD44v6 is mainly restricted to T cell blasts. CD44v7 has been detected on CD4(+) cells, B cells and monocytes. Mitogenic and antigenic stimulation of lymphocytes in vitro was impaired in the presence of anti-CD44v6 and anti-CD44v7. Accordingly, anti-CD44v6 and anti-CD44v7 mitigated the DTH reaction in 2,4-dinitro-1-fluorobenzene-sensitized and challenged mice. However, the seemingly similar effects of CD44v6- and CD44v7-specific antibodies resulted from different activities. Anti-CD44v6 treatment led to a down-regulation of IL-2 and IFN-gamma production predominantly by CD8(+) cells. In anti-CD44v7-treated mice expression of IL-12 was decreased. Elevated levels of IL-10 accompanied this reduction. The latter resulted from an anti-CD44v7-mediated blockade of interactions between CD4(+) cells and monocytes as well as an active triggering of B cells. Thus, anti-CD44v6 and anti-CD44v7 interfere with lymphocyte activation at very specific points. CD44v6 functions predominantly at the T cell level. CD44v7 influences production of proinflammatory cytokines by B cells as well as an interaction between CD4(+) cells and antigen-presenting cells. As CD44 isoforms do not differ in their intracytoplasmatic tail, the distinct activities must result from expression on different leukocyte subsets and interactions with distinct ligands.
Seiter
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Department of Dermatology, University of the Saarland, 66424 Hamburg/Saar, Germany.
Schmidt
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DS
Zöller
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D000818:Animals; D000943:Antigens, Differentiation; D016175:B-Lymphocyte Subsets / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D004139:Dinitrofluorobenzene / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007962:Leukocytes / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology; D020033:Protein Isoforms / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000943:Antigens, Differentiation; D016207:Cytokines; D018960:Hyaluronan Receptors; D007376:Interleukin-2; D020033:Protein Isoforms; D018664:Interleukin-12; D007371:Interferon-gamma; D004139:Dinitrofluorobenzene