Immunoregulatory circuits among T-cell sets. Identification of a subpopulation of T-helper cells that induces feedback inhibition.

Cantor, Harvey; Hugenberger, J; McVay-Boudreau, L; Eardley, Diane D.; Kemp, John D.; Shen, Francis X.; Gershon, Richard K.

doi:10.1084/jem.148.4.871

Cited by 158 publications

(57 citation statements)

References 13 publications

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“…In fact, there is very little information demonstrating how T regulatory cells become activated in vivo. Nevertheless, an important parallel between CD4 and CD8 suppressor cells is the fact that elimination of either population renders mice more susceptible to autoimmunity, which is reminiscent of classical studies showing collaboration between CD4 and CD8 suppressor cells (41,42). Another similarity between CD4 and CD8 suppressor cells is the evidence of TGF-␤-independent mechanisms of suppression.…”

Section: Discussionmentioning

confidence: 84%

Peptide-Specific CD8 T Regulatory Cells Use IFN-γ to Elaborate TGF-β-Based Suppression

Myers

Croft

Kwon

et al. 2005

The Journal of Immunology

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We identified a murine peptide-specific CD8 T regulatory cell population able to suppress responding CD4 T cells. Immunization with OVA, poly(I:C), and anti-4-1BB generated a population of SIINFEKL-specific CD8 T regulatory cells that profoundly inhibited peptide-responding CD4 T cells from cellular division. The mechanism of suppression required IFN-γ, but IFN-γ alone was not sufficient to suppress the responding CD4 T cells. The data show that CD8 T regulatory cells were unable to suppress unless they engaged IFN-γ. Furthermore, even in the absence of recall with peptide, the CD8 T regulatory cells suppressed CD4 responses as long as IFN-γ was present. To examine the effector mechanism of suppression, we showed that neutralizing TGF-β inhibited suppression because inclusion of anti-TGF-β rescued the proliferative capacity of the responding cells. TGF-β-based suppression was dependent completely upon the CD8 T regulatory cells being capable of binding IFN-γ. This was the case, although peptide recall of primed IFN-γ −/− or IFN-γR−/− CD8 T cells up-regulated pro-TGF-β protein as measured by surface latency-associated peptide expression but yet were unable to suppress. Finally, we asked whether the CD8 T regulatory cells were exposed to active TGF-β in vivo and showed that only wild-type CD8 T regulatory cells expressed the TGF-β-dependent biomarker CD103, suggesting that latency-associated peptide expression is not always congruent with elaboration of active TGF-β. These data define a novel mechanism whereby IFN-γ directly stimulates CD8 T regulatory cells to elaborate TGF-β-based suppression. Ultimately, this mechanism may permit regulation of pathogenic Th1 responses by CD8 T regulatory cells.

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Section: Discussionmentioning

confidence: 84%

Peptide-Specific CD8 T Regulatory Cells Use IFN-γ to Elaborate TGF-β-Based Suppression

Myers

Croft

Kwon

et al. 2005

The Journal of Immunology

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“…The kinetics of suppression suggest that the regulatory step occurs early in the generation of the primary antibody response; thus appropriate target cells may not be required or susceptible in responses by primed spleen cells or virgin spleen cells 48 h or more after culture initiation. This implies that the target cell(s), possibly an amplifier T cell, is necessary for the primary, but not the secondary, response and is not the same amplifier T cell involved in the MLR; the precedent for such a difference has been previously suggested (29). Alternatively, the unprimed B cell may be the target cell; further studies to determine the target cells of these Ts cells are in progress.…”

Section: Genetic Restrictions On Haplotype-specific Ts Cell Activitymentioning

confidence: 99%

Haplotype-specific suppression of antibody responses in vitro. I. Generation of genetically restricted suppressor T cells by neonatal treatment with semiallogeneic spleen cells

Sorensen¹,

Pierce²

1981

The Journal of Experimental Medicine

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C57BL/10 mice were injected with semiallogeneic (B10.D2 X C57BL/10)F(1) spleen cells via the anterior facial vein within 24 h of birth to induce tolerance to B10.D2 (H-2(d)) alloantigens. Spleen cells from these mice as adults developed reduced, but significant, mixed lymphocyte and cytotoxic lymphocyte responses in vitro to H-2(d) stimulator cells and these treated mice rejected first-set B10.D2 skin grafts within a normal time-course, indicating that at best only a state of partial tolerance had been induced. Spleen cells from these mice failed to develop antibody responses to a variety of antigens in vitro when H-2(d) macrophages were in the cultures. Partially purified T cells from these neonatally treated mice suppressed primary antibody responses by normal syngeneic spleen cells in the presence of H-2(d) but not other allogeneic macrophages. These radiosensitive, haplotype-specific suppressor T (Ts) cells inhibited primary antibody responses by blocking initiation of the response, but failed to suppress secondary antibody responses and mixed lymphocyte or cytotoxic lymphocyte responses by appropriate responding spleen cells. To activate H-2(d) haplotype-specific Ts cells, stimulation with IA(d) subregion antigen(s) was necessary and sufficient; syngenicity at the I-A subregion of H-2 between the activated Ts cells and target responding spleen cell populations was also necessary and sufficient to achieve suppression. Comparable results have been obtained with spleen cells from BALB/c mice injected as neonates with (B10.D2 × C57BL/10)F(1) spleen cells where IA(b) antigens activate the haplotype-specific Ts cells. Implications for the significance of this population of haplotype-specific Ts cells in immune regulation are discussed and the properties of these Ts cells are compared and contrasted with other antigen-specific and nonspecific Ts cells whose activity is restricted by I- region products.

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“…These amplifier cells might require cell division before becoming fully competent. T lymphocytes that may augment the functions of mature suppressor cells have recently been described (24,31,68,69). Alternatively, Col may interfere with subcellular processes associated with cell motility or communication, thus preventing cell-to-cell interaction between mature suppressor cells and their targets or intermediary lymphocytes.…”

Section: Inability Of Col Tomentioning

confidence: 99%

“…Suppressor cells acting directly upon helper T cells can be induced by other T ceils (24). In addition, HGG-specific-suppressor cells can be inhibited or inactivated by treatment with antisera specific for surface antigens present on suppressor cells, such as antigens coded for in the 1-J region of 1-1-2 (25), and with antisera directed against cell-surface antigens on subsets of T lymphocytes such as Lyt-2 (25,26) and Thy-1 (6,25) antigens.…”

mentioning

confidence: 99%

Induction and mode of action of suppressor cells generated against human gamma globulin. II. Effects of colchicine.

Parks¹,

Shaller²,

Weigle³

1979

The Journal of Experimental Medicine

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The ability of colchicine (Col) to interfere with suppressor cells specific for the soluble protein antigen human gamma globulin (HGG) has been examined. This interference may be the mechanism of the adjuvanticity promoted by Col. When injected into A/J mice at the appropriate time and concentration, both Col and cyclophosphamide promoted an adjuvant increase in the plaque-forming cell response to 100 micrograms of immunogenic, aggregated HGG. Col abrogated both the induction of suppressor cells when injected with 3 h of tolerization with deaggregated (DHGG) and the expression of previously induced suppressor cells when injected with the antigenic challenge. Interference with the generation and expression of antigen-specific suppressor cells had no detectable effects on the immunologic unresponsive state to HGG. Col did not interfere with the induction of tolerance at a dose (1 mg/kg) that abolished the generation of suppressor cells. Furthermore, the absence of colchicine-sensitive-suppressor cells during the establishment of tolerance had no observable effect on the duration of unresponsivness in either helper T- or B-lymphocyte populations. Finally, Col was not able to terminate the unresponsive state established by DHGG even when responsive splenic B cells could be demonstrated in tolerant animals. These data indicate that suppressor cells are not required for the establishment and maintenance of the unresponsive state to this antigen.

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Immunoregulatory circuits among T-cell sets. Identification of a subpopulation of T-helper cells that induces feedback inhibition.

Cited by 158 publications

References 13 publications

Peptide-Specific CD8 T Regulatory Cells Use IFN-γ to Elaborate TGF-β-Based Suppression

Peptide-Specific CD8 T Regulatory Cells Use IFN-γ to Elaborate TGF-β-Based Suppression

Haplotype-specific suppression of antibody responses in vitro. I. Generation of genetically restricted suppressor T cells by neonatal treatment with semiallogeneic spleen cells

Induction and mode of action of suppressor cells generated against human gamma globulin. II. Effects of colchicine.

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