T cell-dependent suppression of antibody production. I. Characteristics of suppressor T cells following tolerance induction

The T cell hyperproliferation and autoimmune phenotypes that manifest in mice lacking E3 ubiquitin ligases such as Cbl, ITCH, or GRAIL highlight the importance of ubiquitination for the maintenance of peripheral T cell tolerance. Less is known, however, about the deubiquitinating enzymes that regulate T cell proliferation and effector function. Here, we define a cell intrinsic role for the deubiquitinase Usp9X during proximal TCR signaling. Usp9X-deficient T cells were hypoproliferative, yet mice with T cell–specific Usp9x deletion had elevated numbers of antigen-experienced T cells and expanded PD-1 and OX40-expressing populations consistent with immune hyperactivity. Aged Usp9x KO mice developed lupus-like autoimmunity and lymphoproliferative disease, indicating that ubiquitin ligases and deubiquitinases maintain the delicate balance between effective immunity and self-tolerance.

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Immunologically mediated regression of a murine lymphoma after treatment with anti-L3T4 antibody. A consequence of removing L3T4+ suppressor T cells from a host generating predominantly Lyt-2+ T cell-mediated immunity.

Journal of Experimental Medicine ◽

10.1084/jem.168.6.2193 ◽

1988 ◽

Vol 168 (6) ◽

pp. 2193-2206 ◽

Cited By ~ 75

Author(s):

M Awwad ◽

R J North

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Regression ◽

Cell Mediated Immunity ◽

Complete Regression ◽

Suppressor T Cells ◽

Antibody Treatment ◽

P815 Mastocytoma ◽

Thymectomized Mice

This study shows that intravenous injection of 1 mg of anti-L3T4 mAb (GK1.5) into thymectomized mice bearing the syngeneic L5178Y lymphoma results, after a delay of 2-3 d, in complete regression of this tumor and in long-term host survival. A flow cytofluorometric examination of the spleen cells of mAb-treated mice revealed that antibody treatment resulted in the elimination of greater than 98% of L3T4+ T cells, but had no effect on the Lyt-2+ T cells subset. Tumor regression was immunologically mediated, because L5178Y lymphoma cells were shown to be L3T4-, and regression of the tumor failed to occur in mice that had been lethally irradiated before anti-L3T4 mAb was given. Tumor regression was mediated by tumor-sensitized Lyt2+ T cells, as evidenced by the finding that treatment of tumor-bearing mice with anti-Lyt-2 mAb alone, or in combination with anti-L3T4 mAb, resulted in enhancement of tumor growth and a significant decrease in host survival time. Moreover, the spleens of mice whose tumors were undergoing regression in response to anti-L3T4 mAb treatment contained Lyt-2+ T cells capable, on passive transfer, of causing regression of a tumor in recipient mice. These results can be interpreted as showing that removal of tumor-induced L3T4+ suppressor T cells results in the release of Lyt-2+ effector T cells from suppression, and consequently in the generation of enough Lyt-2+ T cell-mediated immunity to cause tumor regression. This can only be achieved, however, if immunity to the tumor is mediated exclusively by Lyt-2+ T cells, as is the case for the L5178Y lymphoma. In the case of the P815 mastocytoma, treatment with anti-L3T4 mAb was without a therapeutic effect, and this was in keeping with the finding that immunity to this tumor is mediated by L3T4+, as well by Lyt-2+ T cells.

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CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021429 ◽

2002 ◽

Vol 197 (1) ◽

pp. 19-26 ◽

Cited By ~ 27

Author(s):

Melanie S. Vacchio ◽

Richard J. Hodes

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Tolerance Induction ◽

Peripheral Tolerance ◽

Cd8 Cells ◽

Costimulatory Signal ◽

Cd28 Costimulation

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

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Regulatory functions of hapten-reactive helper and suppressor T lymphocytes. II. Selective inactivation of hapten-reactive suppressor T cells by hapten-nonimmunogenic copolymers of D-amino acids, and its application to the study of suppressor T-cell effect on helper T-cell development

Journal of Experimental Medicine ◽

10.1084/jem.146.1.91 ◽

1977 ◽

Vol 146 (1) ◽

pp. 91-106 ◽

Cited By ~ 10

Author(s):

T Hamaoka ◽

M Yoshizawa ◽

H Yamamoto ◽

M Kuroki ◽

M Kitagawa

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

T Cell Development ◽

Cell Activity ◽

Helper T Cells ◽

Suppressor T Cells ◽

Helper T Cell ◽

Suppressor T Cell ◽

Suppressor T Lymphocytes

An experimental condition was established in vivo for selectively eliminating hapten-reactive suppressor T-cell activity generated in mice primed with a para-azobenzoate (PAB)-mouse gamma globulin (MGG)-conjugate and treated with PAB-nonimmunogenic copolymer of D-amino acids (D- glutamic acid and D-lysine; D-GL). The elimination of suppressor T-cell activity with PAB-D-GL treatment from the mixed populations of hapten- reactive suppressor and helper T cells substantially increased apparent helper T-cell activity. Moreover, the inhibition of PAB-reactive suppressor T-cell generation by the pretreatment with PAB-D-GL before the PAB-MGG-priming increased the development of PAB-reactive helper T-cell activity. The analysis of hapten-specificity of helper T cells revealed that the reactivity of helper cells developed in the absence of suppressor T cells was more specific for primed PAB-determinants and their cross-reactivities to structurally related determinants such as meta-azobenzoate (MAB) significantly decreased, as compared with the helper T-cell population developed in the presence of suppressor T lymphocytes. In addition, those helper T cells generated in the absence of suppressor T cells were highly susceptible to tolerogenesis by PAB-D- GL. Similarly, the elimination of suppressor T lymphocytes also enhanced helper T-cell activity in a polyclonal fashion in the T-T cell interactions between benzylpenicilloyl (BPO)-reactive T cells and PAB- reactive T cells after immunization of mice with BPO-MGG-PAB. Thus inhibition of BPO-reactive suppressor T-cell development by the BPO-v-GL- pretreatment resulted in augmented generation of PAB-reactive helper T cells with higher susceptibility of tolerogenesis to PAB-D-GL. Thus, these results support the notion that suppressor T cells eventually suppress helper T-cell activity and indicate that the function of suppressor T cells related to helper T-cell development is to inhibit the increase in the specificity and apparent affinity of helper T cells in the primary immune response. The hapten-reactive suppressor and helper T lymphocytes are considered as a model system of T cells that regulate the immune response, and the potential applicability of this system to manipulating various T cell-mediated immune responses is discussed in this context.

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Autologous mixed lymphocyte reaction in human cord blood lymphocytes: Decreased generation of helper and cytotoxic T-cell functions and increased proliferative response and induction of suppressor T cells

Cellular Immunology ◽

10.1016/0008-8749(82)90160-5 ◽

1982 ◽

Vol 66 (1) ◽

pp. 88-98 ◽

Cited By ~ 15

Author(s):

Ronald Palacios ◽

Ulf Andersson

Keyword(s):

T Cells ◽

T Cell ◽

Proliferative Response ◽

Mixed Lymphocyte Reaction ◽

Cytotoxic T Cell ◽

Suppressor T Cells ◽

Autologous Mixed Lymphocyte Reaction ◽

Human Cord Blood ◽

Cell Functions ◽

Cord Blood Lymphocytes

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The Role of TNFR2 and DR3 in the In Vivo Expansion of Tregs in T Cell Depleting Transplantation Regimens

International Journal of Molecular Sciences ◽

10.3390/ijms21093347 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3347

Author(s):

Jose-Ignacio Rodriguez-Barbosa ◽

Pascal Schneider ◽

Luis Graca ◽

Leo Bühler ◽

Jose-Antonio Perez-Simon ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Allogeneic Bone Marrow Transplantation ◽

Tumor Necrosis Factor Receptor ◽

Tolerance Induction ◽

Homeostatic Proliferation ◽

Allogeneic Bone ◽

Transplant Tolerance ◽

Conditioning Regimens

Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self and non-self through cell-intrinsic and cell-extrinsic mechanisms. Peripheral Tregs survival and clonal expansion largely depend on IL-2 and access to co-stimulatory signals such as CD28. Engagement of tumor necrosis factor receptor (TNFR) superfamily members, in particular TNFR2 and DR3, contribute to promote peripheral Tregs expansion and sustain their survival. This property can be leveraged to enhance tolerance to allogeneic transplants by tipping the balance of Tregs over conventional T cells during the course of immune reconstitution. This is of particular interest in peri-transplant tolerance induction protocols in which T cell depletion is applied to reduce the frequency of alloreactive T cells or in conditioning regimens that allow allogeneic bone marrow transplantation. These conditioning regimens are being implemented to limit long-term side effects of continuous immunosuppression and facilitate the establishment of a state of donor-specific tolerance. Lymphopenia-induced homeostatic proliferation in response to cytoreductive conditioning is a window of opportunity to enhance preferential expansion of Tregs during homeostatic proliferation that can be potentiated by agonist stimulation of TNFR.

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