CD30 signals integrate expression of cytotoxic effector molecules, lymphocyte trafficking signals, and signals for proliferation and apoptosis

Although CD30 has long been recognized as an important marker on many lymph omas of diverse origin and as activation molecule on B cells and T cells, i ts primary function has remained obscure. We now report that CD30 signals m ay serve to inhibit effector cell activity by integrating gene expression c hanges of several pathways important for cytotoxic NK and T cell effector f unction. In the large granular lymphoma line YT, CD30 signals down-regulate the expression of cytotoxic effector molecules, Fas ligand, perforin, gran zyme B, and abrogate cytotoxicity, c-myc, a regulator of proliferation and an upstream regulator of Fas ligand expression, is completely suppressed by CD30, Furthermore, CD30 signals strongly induce CCR7, suggesting a role fo r CD30 signals in the homing of lymphocytes to lymph nodes, The up-regulati on of Fas, death receptor 3, and TNF-related apoptosis-inducing ligand by C D30 indicates an increase in susceptibility to apoptotic signals whereas up -regulation of TNFR-associated factor 1 and cellular inhibitor of apoptosis 2 protect cells from certain types of apoptosis, Using gene microarrays, 7 50 gene products were induced and 90 gene products were suppressed >2-fold by CD30 signals, Signals emanating from CD30 use both TNFR-associated facto r 2-dependent and -independent pathways. The integration of CD30 signals in a lymphoma line suggests that CD30 can down-modulate lymphocyte effector f unction and proliferation while directing the cells to lymph nodes and incr easing their susceptibility to certain apoptotic signals. These studies may provide a molecular mechanism for the recently observed CD30-mediated supp ression of CTL activity in vivo in a diabetes model.