CD30 Signals Integrate Expression of Cytotoxic Effector Molecules, Lymphocyte Trafficking Signals, and Signals for Proliferation and Apoptosis

Abstract

Although CD30 has long been recognized as an important marker on many lymphomas of diverse origin and as activation molecule on B cells and T cells, its primary function has remained obscure. We now report that CD30 signals may serve to inhibit effector cell activity by integrating gene expression changes of several pathways important for cytotoxic NK and T cell effector function. In the large granular lymphoma line YT, CD30 signals down-regulate the expression of cytotoxic effector molecules, Fas ligand, perforin, granzyme 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 for CD30 signals in the homing of lymphocytes to lymph nodes. The up-regulation of Fas, death receptor 3, and TNF-related apoptosis-inducing ligand by CD30 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, 750 gene products were induced and 90 gene products were suppressed >2-fold by CD30 signals. Signals emanating from CD30 use both TNFR-associated factor 2-dependent and -independent pathways. The integration of CD30 signals in a lymphoma line suggests that CD30 can down-modulate lymphocyte effector function and proliferation while directing the cells to lymph nodes and increasing their susceptibility to certain apoptotic signals. These studies may provide a molecular mechanism for the recently observed CD30-mediated suppression of CTL activity in vivo in a diabetes model.

CD30 triggering by agonistic antibodies regulates CXCR4 expression and CXCL12 chemotactic activity in the cell line L540

“…The classic stimulator, PMA-ion, induced an increase in CXCR4 mRNA (Figure 1), but the surface density of CXCR4 decreased ( Figure 3) primarily because of internalization. 33,44 Moreover, while this work was in progress, Muta et al 27 reported the surprising, unexpected finding that CD30 signals led to a 5.8-fold increase in CCR7 mRNA in YT lymphoma cells, arguing that, through CCR7, CD30 signals integrate lymphocyte trafficking, proliferation, and apoptosis. For personal use only.…”

“…For personal use only. on April 2, 2019. by guest www.bloodjournal.org From Thus, engagement of CD30 by CD153, which is associated preferentially with Th2-type effector responses, 19 regulates CXCR4 and CCR7 27 expression and delivers inhibitory signals, 20,27 leading to impaired clonal expansion of peripheral T cells, 21 sensitizing to TNFR1-dependent apoptosis, 3 and counteracting IgG and IgA production. 52 This cellularlevel regulation seems to have a counterpart in a number of conditions, sharing the tendency to selective compartmentalization of lowproliferating CD30 ϩ cells, which deliver locally anti-inflammatory cytokines, such as IL-4 and IL-10, whenever tested for 16 and which generate a molecular milieu characterized by features of immune suppression.…”

“…24 The role of CD30 in HIV-1 infection, 15,22 the preferential association of CD30 with compartmentalized lymphoid subsets during differentiation 11 and effector responses, 16 and the evidence that Th1 versus Th2 or naive versus primed T cells are distinguished by specific patterns of CD30 8 and chemokine receptor expression 25,26 suggest some kind of relationship between CD30 signals and chemokine function. Recently, Muta et al 27 reported that CD30 signals increased amounts of CCR7 mRNA in the YT lymphoma cell line. Actually, a number of CD30-related activities seem to integrate cellular functions driven by lymphoid chemokines, namely their prototypic member CXCL12 (SDF-1) and its receptor CXCR4 (CD184).…”

Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients

“…CD8ϩ T cells from subjects in group 1 had reduced gene expression of TNF family members, the cell surface expression of which is associated with susceptibility to activationinduced cell death (27,(55)(56)(57)(58)(59), with decreased expression of TNF receptor I (TNFRI), TNFRII, TRAILR-1, CD30 ligand, and Fas ( Figure 3C). In contrast, expression of the gene for IL-15R␣ chain was increased, whereas the gene for IL-2R␥ was decreased ( Figure 3C).…”

Microarray Analysis of Antigen-Dependent B-Cell Activation Gene Expression in Bitches with Pyometra

“…The other important proteins involved in this process include Fas, described also as TNF receptorsuperfamily member 6. Binding of ligand to Fas receptor between Band T cells may negatively modulate activation and proliferation of B cells, leading to induction of B cell apoptosis (12)(13). Furthermore, other molecules like interleukins (including in this study IL-l 0) belong to the family of proteins which are the main modulators of immune response and inflammatory reactions against foreign antigens (14)(15)(16).…”