Clonal anergy induced in mature Vβ6+ T lymphocytes on immunizing Mls-1b mice with Mls-1a expressing cells

Rammensee, Hans‐Georg; Kroschewski, Ruth; Frangoulis, Bernard

doi:10.1038/339541a0

Cited by 434 publications

(209 citation statements)

References 29 publications

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“…4). At birth (5,6,9,11,(19)(20)(21)(22)(23)(24). Likewise, EL singly transgenic mice did not develop spontaneous autoimmunity in exocrine pan- creas.…”

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confidence: 99%

Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice.

Fields

Loh²

1992

Proc. Natl. Acad. Sci. U.S.A.

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The developmental fate of autoreactive T cells encountering extrathymically expressed self-antigen was studied in a doubly transgenic mouse model system where pancreatic acinar cells expressed H-2Ld and T cells expressed an antigen receptor (2C TCR) specific for H-2Ld. Thymocytes bearing 2C TCR differentiated normally. They were positively selected without evidence of intrathymic clonal deletion. Survival of H12Ld-bearing skin allografts was significantly prolonged in pancreatic H-2Ld singly and doubly transgenic mice, consistent with an in vivo state of T-cell tolerance. The mechanism of tolerance induction was determined and found to have two components. First, up to 80% of peripheral CD8+2C TCR+ T cells were eliminated. Second, those T cells which escaped elimination had a signlf cantly reduced proliferative response to H-2Ld. Thus, autoreactive T cells can be made self-tolerant through interaction with self-antigen located extrathymically. This is accomplished by a reduction in the percentage of autoreactive T cells as well as by a reduction in the functional capacity of residual T cells. Surprisingly, although pancreatic lymphocytic infUltration and organ ihjury were absent in exocrine tissue of singly transgenic mice, it was present in doubly transgenic mice. This suggests that when the percentage of autoreactive T cells is high, tolerance induction can be associated with an inflammatory infiltrate in extrathymic tissue where self-antigen is presented.

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“…4). At birth (5,6,9,11,(19)(20)(21)(22)(23)(24). Likewise, EL singly transgenic mice did not develop spontaneous autoimmunity in exocrine pan- creas.…”

mentioning

confidence: 99%

Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice.

Fields

Loh²

1992

Proc. Natl. Acad. Sci. U.S.A.

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“…The availability of TCR transgenic mice (7,8) will allow us to experimentally approach this question . There is already evidence that neonatal tolerization for reactivity to Mls antigens phenotypically abolishes anti-Mls reactivity in vitro and in vivo without clonally deleting the respective Vii-bearing lymphocytes (52).…”

mentioning

confidence: 99%

Induction of peripheral tolerance to class I major histocompatibility complex (MHC) alloantigens in adult mice: transfused class I MHC-incompatible splenocytes veto clonal responses of antigen-reactive Lyt-2+ T cells.

Heeg

Wagner

1990

The Journal of Experimental Medicine

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SummaryThe efficacy and the mode ofaction of pretransplant transfusion with class I major histocompatibility complex (MHC)-disparate splenocytes in establishing a state of peripheral tolerance in adult mice is analyzed. Adult mice injected intravenously with a critical number of N5 x 10' allogenic splenocytes accept skin grafts and develop chimerism in the peripheral lymphatic tissues, but not in thymus and bone marrow. In parallel, a split tolerance evolves : the frequency of class I MHC-reactive Lyt-2+ cytotoxic T lymphocyte precursor (CTIrp)-and interleukin 2 (IIr2)-producing T cells falls off in the peripheral lymphoid tissue, but remains unaltered intrathymically. In particular, high affinity CTLp become clonally undetectable . In vivo generation of tolerant cells is cyclosporin A resistant, but dependent on recipient L3T4+ T cells. Loss of Lyt-2+ CTIrpand IL-2-producing T cell precursors is not due to active suppression, but is caused by clonal anergy. Donor-derived chimeric cells positively selected 7 d after intravenous transfusion exhibit in vitro the hallmarks of veto cells, i.e., paralyze CTLp reactive to donor-type class I MHC alloantigens . We conclude that the peripheral (split) tolerance induced in vivo by pretransplant transfusion operates because donor-type cells develop in vivo efficiently into "veto cells;' which in turn induce a state of clonal anergy within antigen-reactive Lyt-2+ T lymphocytes.A prime aim in transplantation immunology is to define gentle methods able to convert immune reactivity to transplantation antigens into a state of immune unresponsiveness. This conversion is successful in neonates: introduction of foreign antigens into a developing immune system prevents the system from responding further on to these antigens (1, 2). Recent evidence indicates that both in natural tolerance and in experimentally induced neonatal unresponsiveness maturing antigen-reactive thymocytes become either clonally deleted (3-8) or at least clonally silenced (9-11) .Induction of unresponsiveness in a mature peripheral T cell pool meets difficulties : receptor occupancy by antigens primarily induces sensitization rather than tolerization (12)(13)(14) . Therefore, most strategies attempt first to reduce the pool of immunocompetent peripheral T lymphocytes, and thereafter to induce unresponsiveness by exposing the regenerating (neonatal) immune system to antigen . In the first step, rather invasive techniques are used, such as whole body (15, 16) or total lymphoid irradiation (17), systemic application of antiproliferative drugs (18,19), or a combination of either of these methods.Evaluation of pretransplant transfusion effects have indicated that intravenous confrontation with allogeneic cells may induce specific immunosuppression rather than sensitization (20)(21)(22)(23)(24)(25)(26)(27)(28) Miller, Bevan, pioneered the veto cell concept . Accordingly, unlinked to the specificity of their own antigen receptor, veto cells paralyze in vitro the response of T cells reacting to antigens displayed by ...

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“…23 On the other hand, the preimmunization renders anergic Mtv-SAgs-specific T cells. 23,24 Our observations question the role of Mtv-SAgs-specific T cells in GVHD: do they behave as effectors of the reaction or do they mediate an inducer/helper effect? The former hypothesis is unlikely because the injection of T cells collected from LS mice that are reactive to Mtv-SAgs 2-3 months after the graft 18 and of CD4 + T cell clones specific for Mls- cDNA synthetized from CD8 + cells extracted RNA was submitted to PCR amplification using V␤ and C␤ primers.…”

Section: Discussionmentioning

confidence: 91%

Relative importance of CD4+ and CD8+ T cell repertoires in the development of acute graft-versus-host disease in a murine model of bone marrow transplantation

Miconnet

Selle

Bruley-Rosset

1998

Bone Marrow Transplant

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Summary:T cell repertoire alterations occurring after allogeneic BMT and related emergence of aGVHD has not been directly demonstrated. CD4, CD8 and V␤ usage of T cells infiltrating spleen, lymph nodes and liver was compared in lethally irradiated F1(DBA/2 ؋ B10.D2) recipients which develop (GVHD mice) or not (long survivor:LS mice) aGVHD across minor histocompatibility antigens (mHAgs) and Mtv-6 and Mtv-7 encoded superantigens (SAgs) barriers according to experimental conditions. The early expansion in GVHD mice of CD4V␤6 ؉ and of CD4V␤3 ؉ T cell subsets specific for Mtv-7 and Mtv-6 SAgs, respectively, is abolished in LS protected mice. By contrast, CD8 ؉ T cells infiltrate lymph nodes, the liver but not the spleen of LS as in GVHD mice. V␤ subset overexpression is frequent in all T cell phenotypes in GVHD but only among CD8 ؉ T cells in LS mice. Predominant V␤ pattern subpopulation is unique to each mouse. Overexpressed V␤ subpopulation sequencing clearly indicates that expansion results from a very limited number of clones. Association of a given V␤ segment with different J␤ for each mouse suggests that the response is directed towards many different antigens. The data emphasize that MtvSAg and mHAgs CD4 ؉ T cells are of crucial importance during GVHD and that there is no relationship between CD8 ؉ T cell repertoires and pathological status. Keywords: graft-versus-host; repertoire; bone marrow transplantation; minor histocompatibility antigens BMT provides a curative therapy for patients with hematopoietic malignancies but GVHD occurs frequently even in MHC-compatible donor-recipient combinations. [1][2][3] In this situation, the disease results from the recognition of host minor histocompatibility antigens (mHAgs) by donor T lymphocytes. Although T cell depletion of the graft prevents GVHD, 3 this treatment is accompanied by a higher incidence of leukemic relapse. 4 Thus, several studies in mice and in humans have focused on the identification of T cells with the objective of dissociating GVHD and graft- versus-leukemia effect (GVL). Previous data have shown that CD4 + and CD8 + cells are involved in GVHD depending on the nature of the incompatibilities between donor and recipient. 5,6 Detailed analysis of the T cell repertoire has already described frequent alterations consisting of selective expansion of some V␤ subpopulations in the spleen and the liver of mice developing GVHD across minor histocompatibility barriers 7 and also in skin and/or blood of patients following allogeneic BMT. [8][9][10][11][12][13][14] In our experimental model, lethal GVHD develops in irradiated F1(DBA/2 × B10.D2) mice transplanted with MHC identical B10.D2 lymphoid cells 1 incompatible for multiple DBA/2 mHAgs and for Mls-1 a and Mls-2 a superantigens (SAgs) encoded by the endogenous mouse mammary tumor viruses Mtv-7 and Mtv-6, respectively. 15 T cell depletion experiments and clonal analysis have shown that predominantly CD4 +5,16 but also CD8 +5,17 T cells are implicated in the induction of GVHD mortality in this genetic com...

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Clonal anergy induced in mature Vβ6+ T lymphocytes on immunizing Mls-1b mice with Mls-1a expressing cells

Cited by 434 publications

References 29 publications

Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice.

Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice.

Induction of peripheral tolerance to class I major histocompatibility complex (MHC) alloantigens in adult mice: transfused class I MHC-incompatible splenocytes veto clonal responses of antigen-reactive Lyt-2+ T cells.

Relative importance of CD4+ and CD8+ T cell repertoires in the development of acute graft-versus-host disease in a murine model of bone marrow transplantation

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