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Results for “clonal deletion”

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PubMed1997

CD4 regulates the efficiency of an endogenous superantigen-induced clonal deletion of TCRV beta 11+ cells in the periphery.

Peripheral T-cell antigen receptor V beta (TCRV beta) repertoire is influenced by clonal deletion both in the thymus and periphery. Developing thymocytes expressing certain TCRV beta are deleted by endogenous superantigens presented on major histocompatibility complex (MHC) molecules in the thymus. Likewise, mature T cells bearing particular TCRV beta chains can be clonally deleted by superantigens in the periphery. The efficiency with which T cells expressing particular V beta subunits are deleted differs depending upon which coreceptor is expressed. Indeed, while deletion of V beta 11+ splenic T cells in CBA/J (Mls-1, a I-E, + MTV 9+) mice is quite efficient for CD4+ spleen T cells, it is much less efficient for CD8+ splenic T cells. If the difference in the efficiency of deletion is due solely to the coreceptor expressed, then a transgene encoding CD4 should increase the efficiency with which CD8+ cells are deleted. To address this question, we have produced CD4 transgenic (TG) mice that express physiologic levels of CD4 on all thymocytes and peripheral CD8 T cells. CD4 molecules expressed on CD8+ splenic T cells were associated with P56lck tyrosine kinase, and were functional as evidenced by their ability to facilitate class II alloreactivity. Furthermore, we found that ectopic expression of TG CD4 molecules on CD8+ cells was able to affect the efficiency of deletion in response to superantigen stimulation. In particular, deletion of TCRV beta 11+ T cells was much less efficient for CD8+ than for CD4+ T-cell subpopulations in (CBA/J x B6) F1 mice. However, expression of the CD4 transgene on CD8+ splenic T cells from these mice increased the efficiency of deletion in the CD8+ V beta 11 T cells. Interestingly, this effect was not observed in a mature CD8+ thymocyte subpopulation. The results in this report demonstrate that CD4 molecules are involved in peripheral deletion of TCRV beta 11+ T cells in (CBA/J x B6) F1 mice, and that the TCRV beta repertoire can be altered by ectopic expression of CD4 on all T-lineage cells.

Animals↗

PubMed1997

Increased mortality and impaired clonal deletion after staphylococcal enterotoxin B injection in old mice: relation to cytokines and nitric oxide production.

In the present study peripheral T cell tolerance and the occurrence of shock were evaluated in young and old mice after injection of Staphylococcal enterotoxin B (SEB). In young mice SEB immunization leads to tolerance based on deletion and anergy of SEB-reactive V beta 8+ T cells. With aging, mice developed resistance to SEB-induced deletion of V beta 8+ T cells as well as a high sensitivity to toxic shock. Compared to young mice, older mice injected with SEB showed increased serum levels of interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and IL-4. These results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR), as splenic mRNA levels taken 2 h after SEB injection showed higher values of IL-2, IL-4, and IFN-gamma in old mice. In contrast, mRNA levels for FasL and tumour necrosis factor-alpha (TNF-alpha) were lower. No difference in IL-10 mRNA was found. Compared to young mice, old mice showed a high, but statistically not significantly different (P = 0.20), production of nitric oxide (NO). Blocking of IFN-gamma with antibodies or reducing IFN-gamma by depletion of natural killer (NK) cells resulted, respectively, in a complete or partial protection against mortality in aged mice. Suppressing the NO production by the NO synthase inhibitor N-nitro-L-arginine methylester (L-NAME) increased the mortality in both young and old mice, and abrogated clonal deletion in the surviving young mice. In conclusion, in young mice NO production is a key factor in the protection against mortality and the development of clonal deletion after SEB injection. The higher mortality seen in older mice is mainly related to the elevated production of IFN-gamma and occurs despite a sufficient production of NO. The decreased clonal deletion of old mice may be related to their decreased expression of Fas ligand or TNF-alpha after SEB injection.

Aging↗

PubMed1993

Clonal deletion of specific thymocytes by an immunoglobulin idiotype.

We have investigated whether immunoglobulin can induce clonal deletion of thymocytes by employing two strains of transgenic mice. One strain is transgenic for an alpha/beta T cell receptor (TCR) which recognizes a processed idiotypic peptide of the lambda 2(315) light chain variable region, bound to the I-Ed class II major histocompatibility complex molecule. The other mouse strain is transgenic for the lambda 2(315) gene. Double transgenic offspring from a TCR-transgenic female mated with a lambda 2(315) transgenic male exhibit a pronounced clonal deletion of CD4+CD8+ thymocytes. Analysis of neonates from the reciprocal (lambda 2(315)-transgenic female x TCR-transgenic male) cross suggests that the deletion in double transgenic offspring most likely is caused by lambda 2(315) produced within the thymus rather than by maternally derived IgG, lambda 2(315). Nevertheless, IgG, lambda 2(315) can cause deletion of CD4+CD8+ thymocytes when injected in large amounts intraperitoneally into either adult or neonatal TCR-transgenic mice. Deletion is evident 48 and 72 h after injection, but by day 7 the thymus has already regained its normal appearance. A serum concentration of several hundred microgram/ml is required for deletion to be observed. Therefore, the heterogeneous idiotypes of serum Ig are probably each of too low concentration to cause thymocyte deletion in normal animals.

Animals↗

PubMed1987

Pretransplant cytotoxic conditioning produces effects consistent with clonal deletion mechanisms.

A rat cardiac allograft model (ACl to Lewis) was used to investigate the clonal deletion theory. Twelve groups of Lewis recipients received various combinations of donor-specific blood transfusions (DSTs), immediate post-DST immunosuppression with azathioprine/prednisone, and low-dose cyclosporine (1 mg/kg/day) posttransplant. DSTs and cyclosporine together gave modest prolongation of graft survival (from 6.0 to 17 days). DSTs plus immediate post-DST immunosuppression followed by low-dose cyclosporine prolonged graft survival to an average of 45 days. Third-party transfusions alone and in combination with immunosuppression did not significantly prolong allograft survival. Postoperative cyclosporine was required for the expression of this effect suggesting that clonal depression rather than clonal deletion had occurred. Combining DSTs with brief but intense preoperative immunosuppression may be a more effective method of pretransplant conditioning than DSTs alone.

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PubMed1998

Bone marrow transplantation induces either clonal deletion or infectious tolerance depending on the dose.

The concept of immunologic tolerance arose from bone marrow transplantation in neonatal or irradiated mice, in which the predominant mechanism is clonal deletion of donor-specific T cells by donor hemopoietic cells in the recipient thymus. A short term treatment with nonlytic CD4 and CD8 mAbs can induce tolerance to tissue allografts or reversal of spontaneous autoimmunity. Such tolerance to skin or heart allografts is dependent on "infectious" tolerance mediated by regulatory CD4+ T cells. We show here, for multiple minor Ag differences, that while a large inoculum of donor marrow produces significant deletion of Ag-reactive cells as expected, a low marrow dose generates tolerance with little evidence of clonal deletion. Only this low dose tolerance can be transferred to unmanipulated recipients via CD4+ T cells, can be passed onto naive T cells as if infectious, and can act to suppress rejection of third party Ags when "linked" on F1 grafts.

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PubMed1989

The MHC molecule I-E is necessary but not sufficient for the clonal deletion of V beta 11-bearing T cells.

We have generated an mAb, RR3-15, that recognizes murine TCRs containing the V beta 11 domain. Using this antibody to stain peripheral T cells, we have demonstrated that V beta 11-bearing T cells are largely absent from strains of mice that express the class II MHC molecule, I-E. Studies with F1 mice demonstrate that this effect is dominant, consistent with tolerance. The clonal deletion of V beta 11-bearing T cells appears to occur intrathymically, as immature but not mature V beta 11+ T cells are present in the thymus of I-E-bearing mice. Examination of B6 x DBA/2 recombinant inbred strains demonstrates that the expression of I-E molecules is necessary for the clonal deletion of V beta 11-bearing T cells, but that other non-MHC genes control the clonal deletion process, as well. Paradoxically, only a small fraction of V beta 11+ T cell hybridomas are I-E reactive.

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PubMed1981

Functional clonal deletion in immunological tolerance to major histocompatibility complex antigens.

CBA (H-2k) mice were rendered tolerant to H-2d antigens by injection of (CBA X BALB/c)F1 spleen cells at birth. At intervals of 2 days to 12 weeks, the frequencies of anti-H-2d cytotoxic T lymphocyte precursor cells (CTL-P) in thymus and spleen were determined by using a limiting-dilution microculture assay system for CTL-P. This assay, utilizing irradiated H-2d stimulator cells and concanavalin A-induced spleen cell conditioned medium, was shown to be linear over the range 30 to 100,000 responder cells and uninfluenced by IJ-positive cells. A profound and long-lasting deficit in activatable CTL-P, first demonstrable by day 5 of life in the thymus and day 8-10 in the spleen, developed in mice rendered tolerant, reaching a greater than 95% reduction by 6 weeks. Functional clonal deletion thus seems to be at least as important in the tolerant state as suppressor T cells. Repeated in vivo administration of anti-IJk serum partially inhibited clonal deletion, suggesting either that suppressor T cells are actively involved in producing clonal deletion or that IJk-bearing cells in the donor inoculum or the host represent an important factor.

Age Factors↗

PubMed2026

Distributed clonal deletion prevents autoimmune disease progression.

Self-reactive B cells arise during development and can increase pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that self-tolerance is enforced through temporally distinct mitochondrial outer membrane permeabilization (MOMP) checkpoints. Using conditional Bcl-2 expression to inhibit MOMP either from B cell development or activation, we find that early inhibition permits survival of autoreactive B cells after peripheral egress, expanding the pool available for activation and AID-dependent diversification. This results in broadened class-switched IgG autoreactivity, complement activation, kidney pathology, and drives lethal autoimmune disease. In contrast, post-activation MOMP inhibition promotes autoreactive cell accumulation and autoantibody production but causes limited tissue damage and normal survival. Together, these findings support a Distributed Clonal Deletion Model in which temporally distinct checkpoints cooperate to constrain autoimmune disease progression.

AID↗

PubMed1992

Why is clonal deletion of neonatal thymocytes defective?

A major mechanism for establishing tolerance to some murine self antigens is clonal deletion of self reactive T cells in the thymus. This mechanism is responsible for the near absence of T cells displaying particular T cell receptor (TcR) V beta in strains of mice that express the major histocompatibility complex class II E molecule and a protein encoded within the 3' open reading frame (ORF) of certain endogenous mammary tumor viruses (Mtv). However, clonal deletion does not operate in these same strains during the first few days after birth. This defect could be explained by a difference in any (or any combination of) the three elements involved: the T cell, the thymic stromal cell(s) or the antigen. We have explored these different possibilities and have come to the conclusion that a lack of antigen is the most likely explanation. Yet, neonatal and adult thymi have quite similar levels of messenger ribonucleic acid corresponding to Mtv 3' ORF.

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PubMed1992

Characterization of the Mlsf system. II. Identification of mouse mammary tumor virus proviruses involved in the clonal deletion of self-Mlsf-reactive T cells.

The genetic linkage of loci encoding stimulatory Mlsa and Mlsc determinants with proviruses of mouse mammary tumour viruses (MMTV) has been shown. We previously have reported that the ligand(s) for V beta 5, V beta 11, and V beta 12 behaves as a novel minor lymphocyte-stimulating (Mls) determinant(s), Mlsf, to induce the strong proliferation of unprimed T cells, and that this ligand(s) also functions as a self-Ag for the clonal deletion of self-reactive T cells. In the accompanying paper (Part I), a unique polymorphism characteristic of the Mlsf gene product is presented. In order to determine the genetic basis for this novel Mls system, we examined the progeny of multiple genetic crosses to identify the MMTV proviral loci involved in the clonal deletion of self-Mlsf-reactive T cells. Results from these investigations indicated that at least three known MMTV proviruses, Mtv-8, Mtv-9, and Mtv-11 are involved in the expression of Mlsf gene products. Presence of Mtv-9 results in the complete deletion of V beta 5, V beta 11, and V beta 12; Mtv-8 is associated with the complete deletion of V beta 12, but only a partial deletion of V beta 11 (primarily CD4-positive T cell subset) with little or no deletion of V beta 5; and Mtv-11 induces the complete deletion of V beta 11 and V beta 12, but no deletion of V beta 5. Given the significant sequence homology in the C-terminal portion of the open reading frame (ORF) region among these three MMTV and the almost equivalent effect of these three MMTV provirus upon the V beta 12 repertoire, their apparent hierarchic effect upon the V beta 5 and V beta 11 repertoires suggests that affinity differences in recognition of the same determinant by different TCR V beta may play a significant role in the clonal deletion of self-reactive T cells.

Animals↗

PubMed1990

Clonal deletion of self-reactive T cells at the early stage of T cell development in thymus of radiation bone marrow chimeras.

Sequential appearance of T cell subpopulations occurs in the thymocytes of irradiated C3H/He mice (H-2k, Mls-1b2a, Thy-1.2) after transplantation with bone marrow cells of AKR/J mice (H-2k, Mls-1a2b, Thy-1.1) (AKR----C3H chimeras). The donor-derived thymocytes of AKR----C3H chimeras on day 14 after bone marrow transplantation (BMT) contained a large number of blastlike CD4+CD8+ cells which represent relatively immature thymocytes, whereas those on day 21 after BMT consisted of small sized CD4+,CD8+ cells which represent a great part in normal thymocytes. To define the developmental stage at which clonal deletion of self-reactive T cells occurs in adult thymus, we followed the fate of V beta 6- or V beta 11-bearing T cells in the donor-derived thymocytes at the early stage of AKR----C3H chimeras. Mature thymocytes expressing high intensity of V beta 6 or V beta 11, which are involved in recognition of Mls-1a or MHC I-E gene products, respectively, were deleted from the donor-derived thymocytes on day 21. Immature thymocytes expressing low intensity of V beta 6 in CD3low thymocyte fraction decreased in proportion, whereas those expressing low intensity of V beta 11 rather increased in proportion in the donor-derived thymocytes of AKR----C3H chimeras from day 14 to day 21 after BMT. These results suggest that the clonal deletion of V beta 6-positive cells occurs just at the stage of immature CD3lowCD4+CD8+ cells, whereas the clonal deletion of V beta 11-positive cells may begin at the transitional stage from CD3lowCD4+CD8+ cells to CD3high single positive cells. Timing of negative selection of thymocytes may vary in distinct T cells capable of recognizing different self-Ag.

Animals↗

PubMed1991

Human HLA-DQ beta chain presents minor lymphocyte stimulating locus gene products and clonally deletes TCR V beta 6+, V beta 8.1+ T cells in single transgenic mice.

Minor lymphocyte stimulating locus (Mls) gene products in association with mouse major histocompatibility complex (MHC) class II molecules are known to determine the repertoire of T-cell receptor (TCR) in mature T cells. In order to test whether human class II molecules can present mouse Mls, HLA-DQ beta transgenic mice were generated. The expression and function of the DQ beta transgene were studied in the progeny of one selected founder which was H-2f and H-2E negative. In these mice, DQ beta molecules pairing with mouse A alpha chain and invariant chain are expressed on the cell surface in a tissue-specific manner. When the DQ beta gene was bred into the Mls-1a strain DBA/1 (H-2q), T cells bearing V beta 6 and V beta 8.1 TCR were clonally deleted in the thymus of DQ beta+ transgenics but not in DQ beta-negative full sibs. Thus, the data presented here clearly demonstrate that the human MHC DQ beta chain can present Mls in the clonal deletion of T cells. Our results also suggest the requirement for an interaction between CD4 and class II molecules (alpha chain) for clonal deletion of T cells to occur.

Animals↗

PubMed1990

Evidence for involvement of clonal anergy in MHC class I and class II disparate skin allograft tolerance after the termination of intrathymic clonal deletion.

Mechanisms of cyclophosphamide (CP)-induced tolerance to class I (D) and class II (IE) alloantigens were studied. Transplantation tolerance across H-2D plus IE Ag-barriers has been achieved when B10.Thy-1.1 (Kb,IAb,IE-,Db; Thy-1.1) mice were primed i.v. with 9 x 10(7) spleen cells plus 3 x 10(7) bone marrow cells from B10.A(5R) mice (5R; kb,IAb,IEb,Dd; Thy-1.2) and treated i.p. with 200 mg/kg of CP 2 days later. The tolerant state in the early and the late stage was confirmed by prolonged acceptance of donor-type skin grafts, and in vitro unresponsiveness to donor Ag. In the tolerant B10.Thy-1.1 mice treated with 5R cells 28 days earlier and followed by CP, intrathymic clonal deletion of V beta 11+ T cells reactive to IE-encoded antigens was observed in association with intrathymic mixed chimerism. 5R skin survived, however, even after the clonal deletion of V beta 11+ T cells terminated by 180 days after tolerance induction. V beta 11+ T cells, which reappeared in the periphery of the recipient B10.Thy-1.1 mice bearing 5R skin at this stage, were not capable of proliferating in response to receptor cross-linking with V beta 11-specific mAb. Furthermore, the CTL activity against class I (Dd) alloantigens of spleen cells from these tolerant mice was restored by the addition of IL-2 to MLC. Thus, our experiments provide direct evidence that tolerance to both class I (Dd) and class II (IEb) alloantigens by clonal allergy occurs during the termination of intrathymic clonal deletion. These results clearly show practical hierarchy of the mechanisms of transplantation tolerance.

Animals↗

PubMed1990

Intrathymic clonal deletion of V beta 6+ T cells in cyclophosphamide-induced tolerance to H-2-compatible, Mls-disparate antigens.

When C3H (H-2k, Mls-1b) mice were primed intravenously with 10(8) viable spleen cells from AKR (H-2k, Mls-1a) and treated intraperitoneally with 200 mg/kg of cyclophosphamide (CP) 2 d later, not only a long-lasting skin allograft tolerance but also a tolerance in mixed lymphocyte reaction to Mls-1a-encoded antigens was established. The cellular mechanisms of CP-induced tolerance were examined by assessing the V beta 6-bearing T cells that are strongly correlated with reactivity to Mls-1a-encoded antigens bound to MHC class II molecules. At the relatively early stage (2 or 5 wk) after the CP treatment, CD4+-V beta 6+ T cells of C3H origin were preferentially eliminated in the lymph nodes of the tolerant mice, whereas CD8+-V beta 6+ T cells remained. On the other hand, neither CD4+CD8- nor CD4-CD8+ thymocytes bearing a high density of V beta 6 was detected in the chimeric thymus. Namely, in the thymus of the tolerant C3H mice, neither mixed chimerism nor the clonal deletion of the V beta 6-bearing T cells was observed on day 14, whereas both of them were observed on day 35. The clonal deletion and mixed chimerism in the thymus were lasting for greater than 10 wk after the CP treatment. Expression of V beta 6 on the peripheral T cells in the tolerant C3H mice gradually reduced in the process of time. These results strongly suggested that the clonal deletion in the thymus was one of the essential mechanisms in the CP-induced tolerance system.

Animals↗

PubMed1994

Transmission of an Mls-1a-like superantigen to BALB/c mice by foster-nursing on F1 Mls-1bxa mothers. Sex-influenced onset of clonal deletion.

Foster nursing of BALB/c (Mls-1b) mice on (BALB/cxAKR/J)F1 and (BALB/cxDBA/2)F1 (Mls-1bxa), but not on (BALB/cxC57Bl/6)F1 or (BALB/cxC3H/He)F1 (Mls-1bxb mothers, induced the progressive deletion of V beta 6+ and V beta 8.1+ T cells in 50% of the litter. The onset of this Mls-1a-like clonal deletion was markedly sex-influenced, being earlier in females (8-10 wk of age) than in males (32 wk). In both sexes, CD4+ V beta 6+ cells were more affected than CD8+ V beta 6+ cells. Decreases in the percentage of V beta 6+ cells were detected simultaneously in the thymus, lymph nodes, and peripheral blood. Preceding clonal deletion, functional unresponsiveness of CD4+ T cells to Mls-1 a Ags and to anti-V beta 6 Abs could be detected in most young male and female mice. The transmission of the Mls-1a-like superantigen through foster-nursing on (BALB/cxAKR/J)F1 mice correlated with the presence in milk of the mouse mammary tumor virus envelope protein gp52.

Animals↗

PubMed1983

Functional clonal deletion and suppression as complementary mechanisms operative in adult hapten-induced cytotoxic T cell tolerance.

Immunologic tolerance to the hapten TNP was induced in adult mice through the i.v. injection of reactive TNBS. To probe the cellular basis of the tolerant state, splenic cytotoxic T lymphocyte precursors (CTL-P) were stimulated in vitro with haptenated, x-irradiated syngeneic spleen cells in the presence or absence of exogenously added growth factors derived from Concanavalin A-stimulated spleen cell conditioned medium (CAS). The cultures were either conventional bulk cultures or limit dilution cloning cultures. For the latter, cytotoxicity was assessed through a semi-automated, radioautographic 111In-release assay. Suppressive potential was assessed by mixing spleen cells from tolerant mice with normal spleen cells before culture. In the absence of CAS, bulk cultures showed profound tolerance, and suppressive capacity was clearly evident. Suppression was dependent on the presence of TNP-self during culture and affected the generation of CTL from CTL-P and not the effector function of CTL. Cyclophosphamide treatment did not prevent tolerance induction. In the presence of CAS, bulk cultures still showed marked tolerance, but mixing experiments now yielded no evidence of suppression. As documented previously, limit dilution cultures of tolerant spleen cells in the presence of CAS showed a functional clonal deletion of hapten-specific CTL-P. In the absence of CAS, limit dilution cultures became dependent on helper T cells as the limiting element. Tolerant populations showed a diminution of activatable helper T lymphocyte precursors (HTL-P), which may have been due to a functional clonal deletion of HTL-P and/or a concomitant activation of suppressor T cells. Adoptive transfer studies showed that cells from tolerant mice did not detectably influence the number of hapten-specific CTL-P in the spleens of host animals. Taken together, the results suggest that both functional clonal deletion of CTL-P and suppression of HTL-P contribute to the tolerant state induced.

Animals↗

PubMed1994

Mechanism underlying superantigen-induced clonal deletion of mature T lymphocytes.

We observed that peripheral T cells activated in vivo or in vitro by superantigens are susceptible to cell death when their antigen receptor is cross-linked with the appropriate anti-alpha beta TCR mAb. TCR ligation by mAbs specifically drove the T cell clonal deletion in both CD4+ and CD8+ cell subsets. An IL-2/IL-2R interaction seems to be a critical step in predisposing superantigen activated cells to death; in fact, in vivo IL-2R blockade reversed T cell deletion in superantigen plus anti-alpha beta TCR mAb treated mice. TCR ligation by mAbs also produced cell death of the relevant targets in in vitro IL-2 activated T cells. Surprisingly, no T cell deletion was demonstrable in IL-2 activated cells following staphylococcal enterotoxin B--TCR interaction, ruling out the possibility that superantigen in itself can induce cell death. Thus, while superantigen activation opens the cell death program, a subsequent TCR--antigen (self) interaction appears necessary to produce clonal deletion in mature T lymphocytes.

Animals↗

PubMed1998

Clonal deletion of thymocytes as a tumor escape mechanism.

Clonal deletion of thymocytes is a major event in T-cell tolerance and might represent a tumor escape mechanism. Previously, we have shown that class II-restricted, Id-specific, CD4+ T cells in T-cell receptor (TCR)-transgenic mice confer resistance against the MOPC315 plasmacytoma. In this report, we have investigated whether monoclonal immunoglobulin (Ig) produced by a plasmacytoma can induce deletion of thymocytes specific for the variable parts of Ig, i.e., the idiotype (Id). Large numbers of MOPC315 tumor cells were injected s.c. in the TCR-transgenic mice to overwhelm the CD4+ T-cell-mediated protection. When the MOPC315 plasmacytomas reached a weight of approximately 0.5 g (serum myeloma protein M315 about 50 microg/ml), immature CD4+ 8+ and mature CD4+ transgenic thymocytes became progressively deleted. Apoptotic thymocytes were already detectable when tumors were 2 mm in diameter (serum M315: 5 microg/ml, or 0.03 microM). The negative selection was Id-specific, because an Id-negative plasmacytoma failed to induce deletion. Injection of purified MOPC315-myeloma protein (M315) i.p. caused a profound reduction of Id-specific thymocytes. Enriched thymic dendritic cells (DC) from tumor-bearing animals were found to be primed with lambda2(315) and induced apoptosis of thymocytes in vitro. Our results indicate that circulating myeloma protein is processed and presented by thymic antigen-presenting cells (APC), and induces deletion of Id-specific thymocytes. Deletion of tumor-specific thymocytes may represent a tumor escape mechanism in patients with cancers that secrete or shed tumor antigens. The possibility that vaccination with tumor Ig or genes encoding for it may induce tolerance instead of protection should be taken into consideration.

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