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PubMed1996

Identification of a novel RalGDS-related protein as a candidate effector for Ras and Rap1.

Although Ras and Rap1 share interaction with common candidate effector proteins, Rap1 lacks the transforming activity exhibited by Ras proteins. It has been speculated that Rap antagonizes Ras transformation through the formation of nonproductive complexes with critical Ras effector targets. To understand further the distinct biological functions of these two closely related proteins, we searched for Rap1b-binding proteins by yeast two-hybrid screening. We identified multiple clones that encode the COOH-terminal sequences of a protein that shares sequence identity with RalGDS and RGL, which we have designated RGL2. A 158-amino acid COOH-terminal fragment of RGL2 (RGL2 C-158) bound to Ras superfamily proteins which shared identical effector domain sequences with Rap1 (Ha-Ras, R-Ras, and TC21). RGL2 C-158 binding was impaired by effector domain mutations in Rap1b and Ha-Ras. Furthermore, RGL2 C-158 bound exclusively to the GTP-, but not the GDP-bound form of Ha-Ras. Finally, coexpression of RGL2 C-158 impaired oncogenic Ras activation of transcription from a Ras-responsive promoter element and focus-forming activity in NIH 3T3 cells. We conclude that RGL2 may be an effector for Ras and/or Rap proteins.

3T3 Cells↗

PubMed1996

Selective activation of effector pathways by brain-specific G protein beta5.

While multiple G protein beta and gamma subunit isoforms have been identified, the implications of this potential diversity of betagamma heterodimers for signaling through betagamma-regulated effector pathways remains unclear. Furthermore the molecular mechanism(s) by which the betagamma complex modulates diverse mammalian effector molecules is unknown. Effector signaling by the structurally distinct brain-specific beta5 subunit was assessed by transient cotransfection with gamma2 in COS cells and compared with beta1. Transfection of either beta1 or beta5 with gamma2 stimulated the activity of cotransfected phospholipase C-beta2 (PLC-beta2), as previously reported. In contrast, cotransfection of beta1 but not beta5 with gamma2 stimulated the mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways even though the expression of beta5 in COS cells was evident by immunoblotting. The G protein beta5 expressed in transfected COS cells was properly folded as its pattern of stable C-terminal proteolytic fragments was identical to that of native brain beta5. The inability of beta5 to activate the MAPK and JNK pathways was not overcome by cotransfection with three additional Ggamma isoforms. These results suggest it is the Gbeta subunit which determines the pattern of downstream signaling by the betagamma complex and imply that the structural features of the betagamma complex mediating effector regulation may differ among effectors.

Animals↗

PubMed1997

An effector-like function of Ras GTPase-activating protein predominates in cardiac muscle cells.

In contrast to familiar role for Ras in proliferation, we and others previously suggested that Ras also mediates hypertrophy, the increase in cell mass characteristic of post-natal ventricular muscle. We showed that activated (G12R) and dominant-negative (S17N) Ha-Ras regulate "constitutive" and growth factor-responsive genes equivalently, in both cardiac myocytes and non-cardiac, Mv1Lu cells. Here, we attempt to delineate pathways by which Ras exerts this global effect. The E63K mutation, which impairs binding of guanine nucleotide releasing factor to Ras, alleviated suppression by S17N, consistent with sequestration of exchange factors as the mechanism for inhibition. To compare potential Ras effector proteins, we first engineered G12R/D38N, to abolish binding of Raf and phosphatidylinositol-3-kinase and established that this site was indispensable for augmenting gene expression. To distinguish between inhibition of Ras by Ras GTPase-activating protein (GAP) versus a potential effector function of GAP, we tested the effector domain substitution P34R: this mutation, which abolishes GAP binding, enhanced Ras-dependent transcription in Mv1Lu cells, yet interfered with Ras-dependent expression in ventricular myocytes. To examine the dichotomous role of Ras-GAP predicted from these P34R results, we transfected both cell types with full-length GAP, the C-terminal catalytic domain (cGAP), or N-terminal Src homology domains (nGAP). In Mv1Lu cells, cGAP markedly inhibited both reporter genes, whereas GAP and nGAP had little effect. Antithetically, in ventricular myocytes, GAP and nGAP activated gene expression, whereas cGAP was ineffective. Thus, Ras activates gene expression through differing effectors contingent on cell type, and an effector-like function of GAP predominates in ventricular muscle.

Actins↗

PubMed1997

Effector specificity mutants of the transcriptional activator NahR of naphthalene degrading Pseudomonas define protein sites involved in binding of aromatic inducers.

This work reports a genetic analysis of the interactions between NahR, the LysR-type regulator of the NAH operons for biodegradation of naphthalene in Pseudomonas, and its aromatic effectors. Six mutants encoding NahR variants responsive to salicylate analogs such as benzoate, which is not an inducer for the wild type regulator, were isolated with a polymerase chain reaction-based saturation mutagenesis protocol. Most mutants displaying a specific change of effector profile bore single amino acid substitutions within a short protein segment of 60 residues located at the central portion of the NahR sequence. Some of the protein variants exhibited an increased affinity for salicylate and also for otherwise suboptimal effectors, with apparent Ks' values 5-100-fold lower than those of the wild type NahR protein. In addition, all mutants were activated by inducers bearing novel substituents at positions 1 or 2 of the aromatic ring and displayed also an enhanced tolerance to changes at positions 3 and 4. Correlation between mutations in NahR and the structures of the new effectors suggested that protein sites Met116, Arg132, Asn169, and Arg248 are involved in effector recognition and binding during the earlier steps of the process leading to transcriptional activation of cognate NAH promoters.

Bacterial Proteins↗

PubMed1998

Identification of PLC210, a Caenorhabditis elegans phospholipase C, as a putative effector of Ras.

Mammalian Ras proteins regulate multiple effectors including Raf, Ral guanine nucleotide dissociation stimulator (RalGDS), and phosphoinositide 3-kinase. In the nematode Caenorhabditis elegans, LIN-45 Raf has been identified by genetic analyses as an effector of LET-60 Ras. To search for other effectors in C. elegans, we performed a yeast two-hybrid screening for LET-60-binding proteins. The screening identified two cDNA clones encoding a phosphoinositide-specific phospholipase C (PI-PLC) with a predicted molecular mass of 210 kDa, designated PLC210. PLC210 possesses two additional functional domains unseen in any known PI-PLCs. One is the C-terminal Ras-associating domain bearing a structural homology with those of RalGDS and AF-6. This domain, which could be narrowed down to 100 amino acid residues, associated in vitro with human Ha-Ras in a GTP-dependent manner and competed with yeast adenylyl cyclase for binding Ha-Ras. The binding was abolished by specific mutations within the effector region of Ha-Ras. The other functional domain is the N-terminal CDC25-like domain, which possesses a structural homology to guanine nucleotide exchange proteins for Ras. These results strongly suggest that PLC210 belongs to a novel class of PI-PLC, which is a putative effector of Ras.

Amino Acid Sequence↗

PubMed1999

Effector recognition by the small GTP-binding proteins Ras and Ral.

The Ral effector protein RLIP76 (also called RIP/RalBP1) binds to Ral.GTP via a region that shares no sequence homology with the Ras-binding domains of the Ser/Thr kinase c-Raf-1 and the Ral-specific guanine nucleotide exchange factors. Whereas the Ras-binding domains have a similar ubiquitin-like structure, the Ral-binding domain of RLIP was predicted to comprise a coiled-coil region. In order to obtain more information about the specificity and the structural mode of the interaction between Ral and RLIP, we have performed a sequence space and a mutational analysis. The sequence space analysis of a comprehensive nonredundant assembly of Ras-like proteins strongly indicated that positions 36 and 37 in the core of the effector region are tree-determinant positions for all subfamilies of Ras-like proteins and dictate the specificity of the interaction of these GTPases with their effector proteins. Indeed, we could convert the specific interaction with Ras effectors and RLIP by mutating these residues in Ras and Ral. We therefore conclude that positions 36 and 37 are critical for the discrimination between Ras and Ral effectors and that, despite the absence of sequence homology between the Ral-binding and the Ras-binding domains, their mode of interaction is most probably similar.

ATP-Binding Cassette Transporters↗

PubMed2000

Effectors increase the affinity of ADP-ribosylation factor for GTP to increase binding.

The stoichiometry of the binding of GTP to ADP-ribosylation factor (ARF) proteins, normally quite low at approximately 0.05 mol/mol protein, was found to increase to a maximum of 1 mol/mol in the presence of effectors. The mechanism of this action was found to result from the ability of these effectors to increase the affinity of ARF for activating guanine nucleotide triphosphates. The existence of a conformation of ARF with low affinity (>100 micrometer) for GTP is proposed. The actions of effectors to increase the equilibrium binding of GTP is interpreted as evidence that these same effectors interact with and modulate the affinity of the inactive ARF for GTP. A new model for these interactions among ARF, effectors, and GTP is proposed, and a preliminary test in cells is supportive of these observations with relevance to signaling in cells.

ADP-Ribosylation Factors↗

PubMed2000

Mutation of Ha-Ras C terminus changes effector pathway utilization.

In PC12 cells, Ha-Ras modulates multiple effector proteins that induce neuronal differentiation. To regulate these pathways Ha-Ras must be located at the plasma membrane, a process normally requiring attachment of farnesyl and palmitate lipids to the C terminus. Ext61L, a constitutively activated and palmitoylated Ha-Ras that lacks a farnesyl group, induced neurites with more actin cytoskeletal changes and lamellipodia than were induced by farnesylated Ha-Ras61L. Ext61L-triggered neurite outgrowth was prevented easily by co-expressing inhibitory Rho, Cdc42, or p21-activated kinase but required increased amounts of inhibitory Rac. Compared with Ha-Ras61L, Ext61L caused 2-fold greater Rac GTP binding and phosphatidylinositol 3-kinase activity in membranes, a hyperactivation that explained the numerous lamellipodia and ineffectiveness of Rac(N17). In contrast, Ext61L activated B-Raf kinase and ERK phosphorylation more poorly than Ha-Ras61L. Thus, accentuated differentiation by Ext61L apparently results from heightened activation of one Ras effector (phosphatidylinositol 3-kinase) and suboptimal activation of another (B-Raf). This surprising unbalanced effector activation, without changes in the designated Ras effector domain, indicates the Ext61L C-terminal alternations are a new way to influence Ha-Ras-effector utilization and suggest a broader role of the lipidated C terminus in Ha-Ras biological functions.

Actins↗

PubMed2002

Distinct sites on G protein beta gamma subunits regulate different effector functions.

G proteins interact with effectors at multiple sites and regulate their activity. The functional significance of multiple contact points is not well understood. We previously identified three residues on distinct surfaces of Gbetagamma that are crucial for G protein-coupled inward rectifier K(+) (GIRK) channel activation. Here we show that mutations at these sites, S67K, S98T, and T128F, abolished or reduced direct GIRK current activation in inside-out patches, but, surprisingly, all mutants synergized with sodium in activating K(+) currents. Each of the three Gbeta(1) mutants bound the channel indicating that the defects reflected mainly functional impairments. We tested these mutants for functional interactions with effectors other than K(+) channels. With N-type calcium channels, Gbetagamma wild type and mutants all inhibited basal currents. A depolarizing pre-pulse relieved Gbetagamma inhibition of Ca(2+) currents by the wild type and the S98T and T128F mutants but not the S67K mutant. Both wild type and mutant Gbetagamma subunits activated phospholipase C beta(2) with similar potencies; however, the S67K mutant showed reduced maximal activity. These data establish a pattern where mutations can alter the Gbetagamma regulation of a specific effector function without affecting other Gbetagamma-mediated functions. Moreover, Ser-67 showed this pattern in all three effectors tested, suggesting that this residue participates in a common functional domain on Gbeta(1) that regulates several effectors. These data show that distinct domains within Gbetagamma subserve specific functional roles.

Animals↗

PubMed2005

Identification of six novel allosteric effectors of Arabidopsis thaliana aspartate kinase-homoserine dehydrogenase isoforms. Physiological context sets the specificity.

The Arabidopsis genome contains two genes predicted to code for bifunctional aspartate kinase-homoserine dehydrogenase enzymes (isoforms I and II). These two activities catalyze the first and the third steps toward the synthesis of the essential amino acids threonine, isoleucine, and methionine. We first characterized the kinetic and regulatory properties of the recombinant enzymes, showing that they mainly differ with respect to the inhibition of the homoserine dehydrogenase activity by threonine. A systematic search for other allosteric effectors allowed us to identify an additional inhibitor (leucine) and 5 activators (alanine, cysteine, isoleucine, serine, and valine) equally efficient on aspartate kinase I activity (4-fold activation). The six effectors of aspartate kinase I were all activators of aspartate kinase II activity (13-fold activation) and displayed a similar specificity for the enzyme. No synergy between different effectors could be observed. The activation, which resulted from a decrease in the Km values for the substrates, was detected using low substrates concentrations. Amino acid quantification revealed that alanine and threonine were much more abundant than the other effectors in Arabidopsis leaf chloroplasts. In vitro kinetics in the presence of physiological concentrations of the seven allosteric effectors confirmed that aspartate kinase I and II activities were highly sensitive to changes in alanine and threonine concentrations. Thus, physiological context rather than enzyme structure sets the specificity of the allosteric control. Stimulation by alanine may play the role of a feed forward activation of the aspartate-derived amino acid pathway in plant.

Adenosine Triphosphate↗

PubMed2001

VIP and PACAP enhance the in vivo generation of memory TH2 cells by inhibiting peripheral deletion of antigen-specific effectors.

In an immune response, antigen-specific CD4 T cells proliferate and differentiate into effector cells capable to produce large amounts of cytokines upon restimulation. Most effector T cells are later eliminated through antigen-induced cell death (AICD), mediated through FasL/Fas interactions. A low percentage of effector T cells survive and differentiate into long-lived memory cells. Mechanisms must operate not only to destroy no longer needed and even potentially damaging T cells, but also to allow the survival of a small number of activated T cells. Little is known about the factors and mechanisms that regulate the shift from an apoptosis-sensitive to an apoptosis-resistant phenotype. VIP and the structurally related peptide, PACAP, synthesized and/or released in the immune organs act on both innate and adaptive immunity. Recently, VIP and PACAP were shown to inhibit AICD in peripheral CD4 T cells by down-regulating FasL expression. In view of these findings, VIP and PACAP are reasonable candidates for the generation of memory T cells. To test this hypothesis, we analyzed the effects of VIP and PACAP in various models for effector and memory T cells. Our data demonstrate that both neuropeptides promote the in vivo effector function and memory phenotype of Th2, but not Th1 cells, by preferentially inhibiting the clonal deletion of Th2 cells. To our knowledge, this is the first report describing the role of a neuropeptide present in the lymphoid microenvironment on the generation and maintenance of long-lived memory T cells.

Adoptive Transfer↗

PubMed1992

Inhibition of carbohydrate uptake of Onchocerca volvulus infective larvae (L3) by effector cell constituents.

The in vitro killing of Onchocerca volvulus infective third stage larvae (L3) by components of their human hosts' defence mechanisms is not well documented, as no suitable assay exists. Motility is inappropriate as a criterion of larval viability because of the unsteady winding movements of L3. In the present study, a metabolic parameter for larval viability, the uptake of [3H]2-deoxy-D-glucose, was evaluated. To demonstrate the reproducibility and validity of this test, the oxygen radical hydrogen peroxide (H2O2) was applied to viable L3 and the death of L3 demonstrated by a 90% reduction in glucose uptake. The incorporation of glucose by the filarial larvae was also determined after in vitro exposure to lysates of the putative effector cells, i.e. eosinophilic and neutrophilic granulocytes and monocytes. Effector-cell-derived components led to a 30-80% dose-dependent decrease in deoxy-glucose uptake, with a half-maximal effect at about 500 micrograms ml-1. These experiments demonstrate, for the first time, the deleterious impact of effector cell constituents on the metabolic activity of O. volvulus L3. The assay could be used to evaluate the effect of distinct natural or recombinant effector molecules on the viability of O. volvulus infective larvae and to investigate the effect of parasite molecules which interfere with effector mechanisms.

Animals↗

PubMed2006

Combined low dose cyclosporine and prednisone down-regulate natural killer cell-like effector functions of CD8brightCD56+ T cells in patients with active Behçet uveitis.

PURPOSE: To investigate the changes of effector-related phenotypic markers and the natural killer (NK)-like effector functions of CD8(bright)CD56+ T cells in patients with Behçet uveitis after combined cyclosporine and prednisone (Cs/Pd) treatment. METHODS: Ten patients with active Behçet panuveitis and 10 healthy controls were prospectively recruited in this study. The effector-related surface markers (CD27, CD62L, CD11b, HLA-DR, CD94, NKG2D), chemokine receptors (CXCR1, CXCR3, CCR4, CCR5), and intracellular perforin of circulating CD8(bright)CD56+ T cells were determined by flow cytometric analysis before and after two months' treatment. NK-like cytotoxicity of ex vivo CD8(bright)CD56+ T cells against K562 was measured by standard 51Cr release assay. RESULTS: The expression levels of effector-related molecules on CD8(bright)CD56+ T cells normalized after treatment. The expression levels of CXCR1 and CCR5 were down-regulated on CD8(bright)CD56+ T cells after treatment. The amounts of preformed intracellular perforin of CD8(bright)CD56+ T cells were reduced to the normal levels. Furthermore, the NK-like cytolytic capacities of CD8(bright)CD56+ T cells were decreased after treatment. CONCLUSIONS: Our results suggest that the combined Cs/Pd treatments in active Behçet uveitis may downregulate the NK-like effector functions of CD8(bright)CD56+ T cells.

Adult↗

PubMed2000

Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain.

Rab5 regulates endocytic membrane traffic by specifically recruiting cytosolic effector proteins to their site of action on early endosomal membranes. We have characterized a new Rab5 effector complex involved in endosomal fusion events. This complex includes a novel protein, Rabenosyn-5, which, like the previously characterized Rab5 effector early endosome antigen 1 (EEA1), contains an FYVE finger domain and is recruited in a phosphatidylinositol-3-kinase-dependent fashion to early endosomes. Rabenosyn-5 is complexed to the Sec1-like protein hVPS45. hVPS45 does not interact directly with Rab5, therefore Rabenosyn-5 serves as a molecular link between hVPS45 and the Rab5 GTPase. This property suggests that Rabenosyn-5 is a closer mammalian functional homologue of yeast Vac1p than EEA1. Furthermore, although both EEA1 and Rabenosyn-5 are required for early endosomal fusion, only overexpression of Rabenosyn-5 inhibits cathepsin D processing, suggesting that the two proteins play distinct roles in endosomal trafficking. We propose that Rab5-dependent formation of membrane domains enriched in phosphatidylinositol-3-phosphate has evolved as a mechanism for the recruitment of multiple effector proteins to mammalian early endosomes, and that these domains are multifunctional, depending on the differing activities of the effector proteins recruited.

Amino Acid Motifs↗

PubMed1975

On the role of the H-2 histocompatibility complex in determining the specificity of cytotoxic effector cells sensitized against syngeneic trinitrophenyl-modified targets.

Spleen cells cultured with syngeneic trinitrophenyl (TNP)-modified stimulator cells display a cytotoxic effect against syngeneic TNP-modified targets, but not against modified targets from unrelated H-2 haplotypes. Targets that share the K and I region of the H-2 complex with the stimulator (or effector) cell are lysed to the same extent as the specific targets, while targets that share the I region only are not. When only the D region is shared, a weak cytotoxic effect is observed. Therefore, the stimulator (or effector) and target cell must share the K or D but not the I region of the H-2 complex in order for optimal cytotoxicity to occur. Spleen cells sensitized to irradiated TNP-modified H-2-allogeneic cells are cytotoxic to these specific cells. Coculture of F1 hybrid cells with irradiated TNP-modified parental cells result in a cytotoxic effect against only those specific parental cells and not TNP-modified cells from the other parent. The cytotoxic effect of the F1 effector cells in the cell-mediated lympholysis test is blocked by the addition of unlabeled TNP-modified targets that are H-2 syngeneic with the sensitizing parental strain, but not H-2 syngeneic with the other parental strain. These data demonstrate that the specificity of the effector cell in this syngeneic cytotoxicity system is directed against altered self H-2-controlled-gene products, rather than a requirement for sharing of histocompatibility genes between effector and target cell in order for lysis to occur. The role of H-2 antigens in determining the sensitivity of a target cell to T-cell-mediated lysis is discussed.

Animals↗

PubMed1977

Specificity of cytotoxic effector cells directed against trinitrobenzene sulfonate-modified syngeneic cells. Failure to recognize cell surface-bound trinitrophenyl dextran.

Mouse splenic lymphocytes and lymphoid tumor cells were modified with the trinitrophenyl (TNP) group either by treatment with trinitrobenzene sulfonate (TNBS) (which covalently modifies cell surface proteins) or with TNP stearoyl dextran (TSD) (which binds to the cell by noncovalent forces). These cell preparations were compared for their ability to: (a) sensitive syngeneic splenic lymphocytes leading to the generation of cytotoxic effector cells; (b) serve as lysable targets in a 4-h(51)Cr- release assay for effector cells generated in (a); and (c) act as blocking cells in the lysis of TNBS-medified targets lysed by TNP self effector cells generated in (a). In none of these three experimental systems did TSD-medified syngeneic spleen or H-2-matched tumor cells act either as a sensitizing immunogen or as a target antigen, despite the demonstration that quantitatively equivalent mounts of TNP were exposed on the cell surface in the TNBS- and TSD-modified cells. In contrast, TNBS-modified spleen cells sensitized syngeneic lymphocytes to generate effectors against TNBS-modified syageneic targets. Furthermore, TNBS- modified, H-2-matched cells served as specific lysable targets and as inhibiting cells for such effectors. These results indicate that the manner in which TNP is associated with the cell surface is important in the immunogenicity and antigenicity of hapten-modified syngeneic stimulating cells in generating H-2-associated cell-mediated lympholysis (CML) reactions. These findings raise the possibility that a covalent or at least a stable linkage with cell surface proteins (possibly H-2- controlled products) is important for immunological function. Furthermore, these observations do not favor the dual receptor model for H-2-restricted syngeneic CML if it is assumed in such a model that one receptor is specific for the TNP moiety and the second for unmodified self major histocompatibility products.

Animals↗

PubMed1982

Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer.

Neonatal thymectomy during the critical period, 2-4 d after birth, can induce various organ-specific autoimmune diseases including oophoritis in A/J mice. The oophoritis thus induced was passively transferred into neonatal mice by injection of spleen cells obtained from syngeneic donors with the disease. Recipient ovaries were rapidly damaged with remarkable mononuclear cell infiltration and destruction of follicular structures. The phenotype of effector cells responsible for successful adoptive transfer was found to be Thy-1+, Lyt-1+,23-, Ia-, Qa-1-, and was sensitive to antithymocyte serum treatment but resistant to cyclophosphamide treatment or in vitro X-ray irradiation. The compatibility between donor and recipient at the major histocompatibility complex was not required for the effector phase of transfer. The oophoritis induced in BALB/c (nu/+ or +/+) was also shown to be transferred into athymic BALB/c nude mice with resulting ovarian lesion and circulating autoantibodies against oocytes. In this transfer system, the effector cells were also demonstrated to be T cells with the Lyt-1+,23- phenotype. Adoptive transfer experiments in both systems revealed that the destruction of ovaries in postthymectomy autoimmune oophoritis was mediated by Lyt-1 T cells. Whether these T cells can be distinguished from other Lyt-1 cells, such as T helper cells and effector T cells in delayed-type hypersensitivity (DTH), is not clear at present, but the results suggest that the effector mechanisms may be closely related to a DTH reaction.

Animals↗

PubMed1986

Radiation-induced, immunologically mediated regression of an established tumor as an example of successful therapeutic immunomanipulation. Preferential elimination of suppressor T cells allows sustained production of effector T cells.

The results of this study confirm results published by others by showing that sublethal whole-body irradiation of mice bearing immunogenic tumors can result in complete tumor regression. The results show, in addition, that irradiation-induced tumor regression can be prevented by infusion, after irradiation, of Ly-1+,2-,L3T4+ suppressor T cells from the spleens of donors bearing an established tumor, but not by infusion of normal spleen cells. This evidence, plus the demonstration that irradiation fails to cause regression of tumors growing in immunocompetent mice, is consistent with the hypothesis that irradiation-induced regression is immunologically mediated, and that it depends on the ability of irradiation to preferentially eliminate suppressor T cells. By using passive transfer assays to measure the production of effector T cells and suppressor T cells against time of tumor growth, it was shown that irradiation of tumor-bearing mice on day 5 of tumor growth resulted in a failure to generate suppressor T cells on the one hand, and in a sustained production, effector T cells on the other. In other words, irradiation prevented the concomitant antitumor immune response from being downregulated by suppressor T cells. However, giving radiation on day 1 of tumor growth, in contrast to giving it 3-6 d later, caused immunodepression and enhancement of tumor growth. This is in keeping with published evidence showing that, whereas resting effector T cells are highly radiosensitive, antigen-activated effector T cells are relatively radioresistant. It is suggested that the radioresistance of activated effector T cells, coupled with the radiosensitivity of activated suppressor T cells, is the reason for the selectivity of ionizing radiation for suppressor T cells and why a tumor needs to be palpable to undergo regression in response to radiation therapy.

Animals↗