Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma

Tumors could escape an immune attack by inducing peripheral T cell tolerance. To test this, T cell receptor (TCR)-transgenic mice were injected with plasmacytoma cells secreting a highly tumor-specific antigen, a monoclonal immunoglobulin (Ig), for which the transgene-encoded TCR is specific. The TCR recognizes a third hypervariable region idiotypic (Id) peptide of the Ig, presented by a class II molecule on host antigen-presenting cells. The TCR-transgenic mice have previously been shown to be protected against an Id+ plasmacytoma challenge. In the present experiments, the protection was deliberately overwhelmed by subcutaneous injection of large numbers of plasmacytoma cells. Such tumor mice, chronically exposed to increasing amounts of monoclonal Ig, delete Id-specific CD4+ T cells in their peripheral lymphoid organs and in the tumor. The residual CD4+ cells express endogenous, rather than transgene-encoded TCR alpha chains. Peripheral deletion, functional T cells unresponsiveness, and thymocyte deletion are all first detected at the same serum concentration of monoclonal Ig, approximately 50 micrograms/ml (0.3 microM), and become more and more profound as the tumor burden increases. The results suggest that peripheral T cell tolerance to Id could be a tumor escape mechanism in patients with B cell malignancies. In addition, the findings have implications for T cell tolerance to Ig V regions in normal individuals.     

Idiotype immunization combined with granulocyte-macrophage colony-stimulating factor in myeloma patients induced type I, major histocompatibility complex-restricted, CD8- and CD4-specific T-cell responses

Idiotypic structures expressed on the myeloma Ig protein might be regarded as a tumor-specific antigen. Five patients with IgG myeloma were immunized with the purified serum M-component by repeated intradermal injections together with soluble granulocyte-macrophage colony-stimulating factor (GM-CSF). All patients developed an idiotype (Id)-specific T-cell immunity, defined as blood T cells predominantly secreting interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) (type I cells). Id-specific DNA synthesis was induced in one patient. Delayed-type hypersensitivity against the Id was not evoked. The specific IFN-gamma/IL-2 T-cell response was inhibited (46% to 100%) by a major histocompatibility complex (MHC) class I monoclonal antibody (MoAb) in all five patients. A 5% to 37% inhibition by an MHC class II MoAb was seen in four patients. CD4+ as well as CD8+ T cells enriched by magnetic microbeads contained Id-specific cells. The T cells recognized peptides corresponding to the complementarity-determining regions 1, 2, and 3 of the heavy chain of the Id. There was a transient rise of B cells producing IgM anti-idiotypic antibodies in all patients. The results indicate that immunization of myeloma patients using the autologous M-component and soluble GM-CSF may evoke an Id-specific predominantly MHC class I-restricted type I T-cell response.     

Engagement of the B lymphocyte antigen receptor induces presentation of intrinsic immunoglobulin peptides on major histocompatibility complex class II molecules

By means of the clonotypic variable region, the immunoglobulin (Ig) is a tumor-specific antigen on B cell neoplasms. We report that engagement of the B cell antigen receptor (BcR) promotes presentation of peptides derived from the B cell's intrinsic Ig to major histocompatibility complex (MHC) class II-restricted T cells. Thus, anti-Ig endowed normal, ex vivo B lymphocytes from H-2d, Ig constant heavy chain allotype b (IgCHb) mice with the capacity to stimulate an I-Ad-restricted T cell clone which recognizes the gamma 2ab 435-451 allopeptide. The corresponding self gamma 2aa peptide is cryptic and 6000-fold less antigenic than the gamma 2ab allopeptide. Even so, the syngeneic B cell lymphoma A20 which expresses surface(s) IgG2aa, was also recognized by the T cells after BcR ligation. Thus, anti-Ig triggered the disclosure of a cryptic tumor antigen determinant. We propose that autoantigens, by engaging the BcR of self-reactive B cells, induce presentation of intrinsic Ig peptides to which the T helper cell (Th) repertoire is not tolerant. In this way, B cells with anti-self potential may be activated without Th recognition of nominal autoantigen.     

The role of anergy in peripheral T cell unresponsiveness

When a T cell's encounter with specific antigen results in good signaling through the T cell antigen receptor yet does not lead to a proliferative response, the T cell enters a state of nonresponsiveness, or anergy. Anergy induction can result from a number of different situations, including antigen presentation by costimulation-deficient or "non-professional" antigen presenting cells, pharmacological blocking of T cell proliferation, or chronic stimulation of the T cell receptor by antigen. Anergy is a long-lived but temporary state characterized by a profound inability of the T cell to produce IL-2. Other effector functions may be affected to variable degrees. Anergy has been characterized most carefully under in vitro conditions, but several experimental models have demonstrated that T cells can also become anergic in vivo. This mechanism for tolerance induction may help to ensure that any mature autoreactive T cells which escape thymic deletion are unable to respond to host tissues. Furthermore, an understanding of the mechanism of anergy induction will most certainly lead to beneficial clinical applications, including improving graft acceptance and avoiding such deleterious immune responses as autoimmunity and allergy.     

Vitamin E inhibits the intimal response to balloon catheter injury in the carotid artery of the cholesterol-fed rat

BACKGROUND: Human B cells can proliferate in vitro after stimulation with anti-Ig and via the CD40 molecule. Superantigens like SEA which bind to MHC class II antigens on, e.g. B cells can polyclonally activate T cells via interaction with their TcR. The activated T cell subsequently activates the B cells to proliferation and Ig-production. OBJECTIVES: To investigate whether superantigen could be used to direct polyclonal T cell help to human B cells stimulated by antigen in a restricted manner resulting in production of antigen-specific antibodies in vitro. STUDY DESIGN: Purified B cells were preincubated with the antigen in manners allowing crosslinking of surface-Ig. The antigen exposed B cells were then cultured together with autologous CD4+ helper T cells and in the presence of various concentrations of SEA. Antibody production was measured by ELISA after 7-12 days of culture. RESULTS: Antigen-specific activation of B cells could be obtained after stimulating the B cells with antigen or anti-surface-Ig antibodies in the presence of T helper cells and SEA. The degree of B cell activation (proliferation as well as antibody production) depended on the dose of antigen as well as on the dose of SEA used. Increased crosslinking of surface-Ig on antigen-specific B cells enhanced Ig production. Specific antibody production to a secondary recall antigen (tetanus toxoid) and to primary antigens (DNP and GM2) were obtained. The specific B cell response was dependent on contact between T and B cells. CONCLUSION: the results obtained demonstrate that the superantigen SEA can recruit T cell help to human B cells specifically stimulated by antigens, resulting in production of antigen reactive antibodies in vitro.     

Characterization of idiotype-specific I-Ed-restricted T suppressor lymphocytes which confine immunoglobulin class expression to IgM in the anti-alpha (1- > 3) Dextran B 1355 S response of BALB/c mice

The humoral immune response of conventionally raised BALB/c mice to the so-called "thymus independent" antigen alpha (1- > 3) Dextran B 1355 S (Dex) is predominantly of the IgM class. The response is further characterized by Igha allotype linkage and the dominance of the public idiotypes (Id) J558 and MOPC 104. In germfree raised BALB/c and in BALB/c nu/nu mice immunized with the same antigen an additional IgG response of the public Id is observed. Analysis of the regulation of the class expression reveals existence of specific Ts cells in euthymic mice which must have been activated pre- or perinatally by exposure to environmental bacterial antigens. They permit or enforce differentiation of Dex-specific B cells into B gamma memory cells without allowing further development into IgG producing plasma cells. An analogue of these splenic Ts cells has now been cloned and identified as an I-Ed restricted Id-specific T cell with exactly the properties ascribed above to the splenic Ts cells. This paper describes phenotypical and functional properties of the Ts cell clone 178-4. It evaluates this clone's role in controlling efficient anti-bacterial IgM-mediated immunity under conditions where a class switch to IgG antibody production is actively suppressed; possibly as a measure to avoid hazardous autoimmune reactions on the basis of crossreaction and antigenic mimicry between polysaccharide antigens.     

Antigen-dependent and -independent Ca2+ responses triggered in T cells by dendritic cells compared with B cells

Dendritic cells (DCs) are much more potent antigen (Ag)-presenting cells than resting B cells for the activation of naive T cells. The mechanisms underlying this difference have been analyzed under conditions where ex vivo DCs or B cells presented known numbers of specific Ag-major histocompatibility complex (MHC) complexes to naive CD4(+) T cells from T cell antigen receptor (TCR) transgenic mice. Several hundred Ag-MHC complexes presented by B cells were necessary to elicit the formation of a few T-B conjugates with small contact zones, and the resulting individual T cell Ca2+ responses were all-or-none. In contrast, Ag-specific T cell Ca2+ responses can be triggered by DCs bearing an average of 30 Ag-MHC complexes per cell. Formation of T-DC conjugates is Ag-independent, but in the presence of the Ag, the surface of the contact zone increases and so does the amplitude of the T cell Ca2+ responses. These results suggest that Ag is better recognized by T cells on DCs essentially because T-DC adhesion precedes Ag recognition, whereas T-B adhesion requires Ag recognition. Surprisingly, we also recorded small Ca2+ responses in T cells interacting with unpulsed DCs. Using DCs purified from MHC class II knockout mice, we provide evidence that this signal is mostly due to MHC-TCR interactions. Such an Ag-independent, MHC-triggered calcium response could be a survival signal that DCs but not B cells are able to deliver to naive T cells.     

Signals and signs for lymphocyte responses

The adaptive immune response protects us from infection in a world of pathogens that is forever evolving new variants. As the system is built on the generation of an open repertoire of receptors, the recognition of self is unavoidable, and is guarded against by deletion during lymphocyte development of those cells that are specific for ubiquitous self antigens, and the silencing of those that are specific for self antigens only encountered after cells achieve functional maturity in the periphery. This silencing occurs when lymphocytes recognize antigens in the absence of suitable costimulatory molecules. By contrast, when the same cell encounters the same ligand on a cell that expresses costimulatory molecules, it will proliferate and differentiate into an effector cell. These effector cells mediate protective immunity when the antigen is carried by a pathogen, but they can mount autoimmune responses if the antigen is derived from self. The major costimulatory molecules for CD4 T cells appear to be B7 and B7.2 that bind to the CD28 and CTLA-4 receptors on the T cell. The signals from the TCR appear to be integrated with those from the costimulator receptor, and the T cell response depends on the precise nature of these signals, further conditioned by cytokines present in the environment of the responding cell. B cells can be viewed in a similar way, with the costimulatory molecule CD40 ligand and cytokines coming mainly from CD4 helper T cells determining the fate of the responding B cell. The TCR is not simply an on and off switch, since the precise way in which the TCR is ligated determines the differentiation of the T cell and can alter the effector responses of established T cell lines. Thus, the response capabilities of T cells are more flexible than originally believed, and much of this flexibility comes from the interplay of TCR signals and signs from the environment. If the biochemical nature of these differential signaling pathways were known, it might be possible to develop simple pharmacological agents capable of diverting T cell responses from harmful to innocuous by getting the T cell to reinterpret the signals it is receiving via its receptors.(ABSTRACT TRUNCATED AT 400 WORDS)     

Fc gamma receptor II dependency of enhanced presentation of major histocompatibility complex class II peptides by a B cell lymphoma

Here we show that the B cell lymphoma A20.292 is capable of enhanced antigen presentation to CD4+ T cells in the presence of specific antibodies. This enhancement was inhibited by anti-Fc gamma receptor (R) antibodies, suggesting that it might be due to preferential uptake of the antigen/antibody complex through the Fc gamma RII receptor. However, immunoprecipitation studies revealed that the FcR of A20.292 cells was of the B cell type, Fc gamma RIIb1, which is not thought to be able to internalize antigen/antibody complexes via clathrin-coated pits. It was considered unlikely that A20.292 had an altered form of the B cell Fc gamma R (RIIb1) receptor that enabled internalization, since similar enhancing effects were also observed using an Fc gamma RII cell line that had been transfected with Fc gamma RIIb1. To reconcile these findings with the expression of Fc gamma RIIb1, it is postulated that immune complexes are concentrated on the cell surface by the Fc gamma RIIb1 and are thus available for preferential uptake by random fluid-phase endocytosis. This results in more efficient generation of the epitopes recognized by these T cell hybridomas.     

CD4+ T cell responses in mice lacking MHC class II molecules specifically on B cells

The role of B lymphocytes in initiating and maintaining a CD4+ T cell response has been examined using a variety of strategies, but remains controversial because of weaknesses inherent to each of the approaches. Here, we address this issue by measuring CD4+ T cell priming both in mutant mice devoid of B cells and in chimeric animals lacking major histocompatibility complex class II molecules specifically on B cells. We find that peptide and some protein antigens do not require B cells expressing class II molecules, nor B cells themselves, to efficiently prime. This could be demonstrated by the usual lymph node proliferation assay, a rather indirect in vitro measure of priming, and by a direct ex vivo assay of population expansion and activation marker expression. Interestingly, one protein antigen, conalbumin, could not prime in the absence of B cells, but could in the presence of B cells devoid of class II molecules. This finding constrains the possible mechanisms whereby B lymphocytes contribute to the initiation of a CD4+ T cell response, arguing against the importance of surface immunoglobulin-mediated antigen presentation by B cells.     

The T cell surface protein, CD28

The cluster of differentiation (CD) antigen CD28 is a 44-kDa, disulphide-bonded, homodimeric glycoprotein, which is constitutively expressed on the surface of all murine T cells and the majority of human T cells. Ligation of CD28 by its counter receptor, B7, expressed on the surface of antigen presenting cells, has been shown to induce signals that, in synergy with those derived from engagement of the T cell receptor by an antigen bound to a major histocompatibility complex, enhance proliferation and cytokine production. Manipulation of this interaction can have dramatic effects on the outcome of T cell activation. Blocking CD28/B7 interactions may be useful in preventing unwanted activation in allergy and autoimmune diseases, whereas enhancing this interaction can promote tumour rejection. Thus, CD28 and its signalling pathways may prove to be useful targets in the development of new therapeutic treatments.     

T-cell activation induced by anti-CD3 x anti-B-cell lymphoma monoclonal antibody is enhanced by pretreatment of lymphoma cells with soluble CD40 ligand

T cells play a key role in the control of abnormal B cell proliferation. Factors that play a role in inadequate T cell responses include absence of expression of costimulatory and adhesion molecules by the malignant B cells and lack of cytotoxic T cells specific for tumor-associated antigens. A number of approaches have been used to enhance T cell response against malignant B cells. Agents such as soluble CD40 ligand can enhance expression of costimulatory molecules by the malignant B cells and improve their ability to activate T cells. Anti-CD3-based bispecific antibodies can retarget T cells toward the tumor cells irrespective of T cell specificity. We used the V 38C13 murine lymphoma model to assess whether the combination of soluble CD40 ligand and anti-CD3-based bispecific antibody can enhance T cell activation induced by malignant B cells more effectively than either approach alone. Expression of CD80, CD86, and ICAM-1 on lymphoma cells was up-regulated by soluble CD40 ligand. Syngeneic T cells were activated more extensively by lymphoma cells when the lymphoma cells were pre-treated with soluble CD40 ligand. Bispecific-antibody induced T cell activation was more extensive when lymphoma cells pretreated with soluble CD40 ligand were present. The combination of soluble CD40 ligand plus bispecific antibody enhanced the median survival of mice compared to mice treated with bispecific antibody alone. We conclude that pretreatment of tumor cells with agents capable of inducing costimulatory molecule expression, such as soluble CD40 ligand can enhance the ability of malignant B cells to activate T cells. This effect is enhanced by the addition of bispecific antibody. The combination of enhanced expression of costimulatory molecules and retargeting of T cells by bispecific antibody may allow for a more effective T-cell-based immunotherapy.     

Evidence for clonal deletion and clonal anergy after intrathymic antigen injection in a transplantation model

Intrathymic (IT) antigen injection has been shown to induce antigen-specific systemic tolerance in the rodent. To delineate the mechanisms responsible for the induction of tolerance, we used the 2C line of T cell receptor transgenic mice. The majority of T cells in 2C mice express an antigen receptor specific for the major histocompatibility complex class I alloantigen Ld and can be identified with the clonotypic monoclonal antibody 1B2. IT injection of lymphoid cells expressing Ld was found to induce a significant prolongation in BALB/c skin allograft survival. The allograft prolongation was associated with a marked reduction in the number of developing 1B2+ thymocytes (clonal deletion), which occurred primarily at the CD4+ CD8+ stage of thymocyte development, as well as a reduction in the number of mature CD8+ 1B2+ 2C T cells in peripheral lymphoid tissue. In addition, CD8+ 1B2+ 2C T cells that survive deletion have decreased CD8 expression levels and a significantly reduced in vitro proliferative response to specific alloantigen (clonal anergy). Exogenous recombinant interleukin 2 restores the capacity of 2C T cells to respond in vitro to alloantigen. Experiments involving separation of cells by fluorescence-activated cell sorter indicate that there is a precise correlation between the reduction in CD8 expression and anergy induction. Collectively, these data indicate that IT antigen injection can induce antigen-specific systemic tolerance by both clonal deletion and clonal anergy.     

The J558 VH CDR3 region contributes little to antibody avidity; however, it is the recognition element for cognate T cell control of the alpha(1-->3) dextran-specific antibody response

Analysis of the humoral immune response of BALB/c mice to alpha(1-->3) dextran (Dex) reveals novel aspects of T cell-mediated control of 'type 2 thymus-independent' responses against polysaccharide antigens. The IgM and IgG antibody response, dominated by the J558 idiotype (Id), is controlled by Id-specific T cells. These regulatory T cells, for which the T cell clone 178-4 Ts with characterized TCR alpha and beta chain sequences is the prototype, expand in all BALB/c mice upon immunization with Dex. They suppress in a cognate interaction the expansion of J558 Id-bearing B cells, committed for production of IgG antibodies. Furthermore they provide a gate which precludes variability in the VH CDR3 region of IgG antibodies appearing occasionally in the periphery. The VH CDR3 region is the recognition element of 178-4 Ts analogous T cells but contributes little to affinity for the antigen. For recognition by 178-4 Ts cells not even minimal sequence deviations of the J558 Id peptide are allowed. The tight germline programmed complementarity between J558 Id-bearing Dex-specific B and J558 Id-specific 178-4 Ts analogous T cells leaves little room on both sides for ontogenetic variability.     

Induction of cross-reactive antibodies against a self protein by immunization with a modified self protein containing a foreign T helper epitope

Self proteins are handled in the same way as foreign proteins by antigen presenting cells, but because of T-cell tolerance the presentation of self peptides does not normally lead to T cell activation. By providing physically linked T-cell help it is possible to overcome the B cell non-responsiveness toward self antigens. We have shown previously that a very potent antibody response, cross-reactive with a self protein, can be rapidly induced by immunizing with a recombinant immunogen consisting of the self protein with a foreign immunodominant T helper epitope inserted into its sequence (Dalum, I., Jensen, M. R., Hindersson, P., Elsner, H. I. and Mouritsen, S. (1996) J. Immnunol. 157, 4796). In this study we compare this approach for inducing autoantibodies against a self protein with the traditional method of conjugating the self antigen to a foreign carrier protein. The highly conserved self protein ubiquitin with an inserted epitope from ovalbumin (UbiOVA) is used as a model protein and compared to two traditionally conjugated immunogens consisting of ubiquitin chemically conjugated to a peptidic T helper epitope or to ovalbumin. The traditionally conjugated immunogens induce much slower and low titered ubiquitin specific antibody responses than the recombinant construct which also is capable of inducing antibodies directed against a much broader range of potential ubiquitin B cell determinants than the chemically conjugated immunogens. All three constructs are processed by antigen presenting cells and ovalbumin derived T cell epitopes are presented to T helper cells. From these observations it seems likely that the presence of non-shielded autologous B cell determinants on the immunogen is critical for the ability to induce a strong autoantibody response with a diverse fine specificity. Furthermore, the ubiquitin specific antibodies induced by UbiOVA contain higher levels of IgG2a/b relative to IgG1 compared to the conjugates. We therefore speculate that the insertion of a T cell epitope directly into the self antigen could possibly induce an immune response with a different Th1/Th2 balance than a response induced with traditional conjugates.     

Impaired male sexual development in perinatal Sprague-Dawley and Long-Evans hooded rats exposed in utero and lactationally to p,p''-DDE

The evolution of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a multi-stage process, comprising the sequential development of chronic H. pylori-associated gastritis, low grade and high grade lymphoma. The genesis of MALT lymphoma embodies the mechanisms of both physiological immune responses and the acquisition of genetic abnormalities. The tumour probably originates from an autoreactive MALT marginal zone B cell, which is generated during H. pylori infection. As a consequence of a genotoxic insult induced by H. pylori infection, the progenitor tumour cell may become genetically unstable and develop genetic abnormalities such as the t(11;18) translocation, trisomy three, c-myc and p53 mutations during a phase of expansion, which lead to partial transformation. With the growth help from H. pylori specific T cells, this abnormal B cell clone may undergo clonal expansion and gradually form a low grade MALT lymphoma. Additional genetic abnormalities including the t(1;14) translocation and other uncharacterised events could completely transform this abnormal B cell clone and result in escape from T cell dependency. Finally, further genetic events such as complete inactivation of the tumour suppressor genes p53 and p16, and possible activation of c-myc oncogene by translocation or other undetermined abnormalities can result in high grade transformation     

The B7/BB1 antigen is expressed by Reed-Sternberg cells of Hodgkin's disease and contributes to the stimulating capacity of Hodgkin's disease-derived cell lines

The B7/BB1 molecule has recently been found to be expressed on professional antigen-presenting cells and to be the natural ligand for CD28 and CTLA-4 on T cells. On binding of B7/BB1, CD28 transduces a signal that synergizes with triggering of the T-cell antigen receptor, resulting in enhanced cytokine secretion. In view of the data supporting an antigen-presenting function of Reed-Sternberg cells, we evaluated the expression of B7/BB1 in lymph nodes affected by Hodgkin's disease. B7/BB1 was found to be strongly expressed by the Reed-Sternberg cells in all 47 cases of Hodgkin's disease studied. Moreover, Reed-Sternberg cells were frequently surrounded by CD28-expressing T cells. Evidence for a functional role of B7/BB1 on Reed-Sternberg cells was obtained by our findings that T-cell proliferation and interleukin-2 (IL-2) production in the primary allogenic mixed lymphocyte reaction (MLR), using the B7/BB1-expressing Hodgkin's disease-derived cell lines L428 and KM-H2 as stimulators, could be partially blocked by adding anti-B7 monoclonal antibody. B7/BB1 expression was also evaluated in a group of non-Hodgkin's lymphomas (n = 46). Whereas B7/BB1 was not expressed by the neoplastic cells of most non-Hodgkin's lymphomas, including T-cell-rich B-cell lymphoma (n = 11), it was present on the neoplastic cells of anaplastic large-cell lymphoma (Ki-1 lymphoma) (n = 5) and follicular lymphoma (n = 4). Our data provide further evidence for an accessory cell function of Reed-Sternberg cells. The accessory cell function of Reed-Sternberg cells might lead to pronounced T-cell activation in vivo, which might contribute to the Hodgkin's syndrome. In addition, our study indicates that B7/BB1 may be a useful marker for differentiating Hodgkin's disease from morphologically similar conditions such as T-cell-rich B-cell lymphoma.     

MHC-specific graft-protective and delayed-type hypersensitivity (DTH) suppressive activity of a CD4+ CD8+, alpha beta T cell receptor (TCR) positive lymphoma isolated from a tolerant mouse

Two lymphomas were found in, and isolated from A (H-2a) mice in which permanent transplantation tolerance was induced to CBA (H-2k) histocompatibility antigens by the neonatal injection of (CBAxA)F1 spleen cells. They proved to be of recipient origin and were transferable to syngeneic A mice, growing as disseminated lymphomas (L33 and L46) and killing the recipients rapidly. Analysis of the cell surface antigens disclosed that both lymphomas had an immature T cell phenotype [Thy-1+, CD5+, CD3low, TCR alpha beta low, CD4low, CD8high, heat-stable antigen (HSA) positive, and CD44-, MHC class II-, CD45R-, sIg-, Gr-1-, CD11b-]. Intraperitoneal (i.p.) injection of syngeneic A mice with viable L33 lymphoma cells resulted in a dose-dependent, significant prolongation of the mean survival times of "specific" CBA and MHC-identical B10.BR skin allografts as compared to the survival of appropriate grafts in non-lymphoma-bearing controls. The survival times of third party MHC-incompatible B10 (H-2b) and B10.D2 (H-2d) allografts were only slightly prolonged in A mice inoculated with L33 cells. The graft-protective effect was not abrogated if the proliferative capacity of the L33 cells was blocked by in vitro mitomycin C (MMC) pretreatment. Furthermore, the inoculation of L33 lymphoma into A mice significantly inhibited their DTH response to the sensitizing CBA histocompatibility antigens. In contrast, the L46 lymphoma had no effect on the survival of CBA allografts and the DTH reactivity. These data suggest that the CD4+CD8+TCR alpha beta + L33 T cell lymphoma originating from a neonatally tolerant mouse has a specific immunosuppressive effect on the in vivo reactivity of syngeneic mice to the tolerance-inducing (MHC class I) alloantigens.     

Kinetics of the response of naive and memory CD8 T cells to antigen: similarities and differences

We have studied the kinetics of the antigen induced response of naive and memory CD8 T cells expressing a transgenic T cell receptor (TCR) specific for the glycoprotein peptide amino acid 33-41 (GP33) of the lymphocytic choriomeningitis virus (LCMV). Memory T cells were generated in vivo by adoptive transfer of LCMV TCR transgenic T cells into normal recipient mice, followed by LCMV infection. The results demonstrated that the cell cycle progression and kinetics of TCR down-modulation, CD25 and CD69 up-regulation were identical in naive and memory T cells after antigen recognition. Moreover, the two T cell populations did not differ in respect of activation thresholds and in their proliferative capacities neither in vitro nor in vivo. However, memory CD8 T cells could be more rapidly induced to become cytolytic and to secrete high levels of interleukin-2 and interferon-gamma than naive T cells. LCMV GP33-specific CD8 memory T cells were only slightly more efficient in reducing LCMV titers in the spleen but were far more effective than naive LCMV GP33-specific T cells in controlling subcutaneous tumor growth of B16.F10 melanoma cells which expressed the LCMV GP33 epitope as tumor-associated antigen. Thus, in our experiments the main difference between CD8 memory T cells and naive cells is the ability of the former to rapidly acquire effector cell functions.