Immunoregulatory circuits among T-cell sets. I. T-helper cells induce other T-cell sets to exert feedback inhibition.

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

doi:10.1084/jem.147.4.1106

Cited by 375 publications

(115 citation statements)

References 14 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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“…Therefore, this type of T-T interaction plays a physiological role in the regulation of the in vivo immune response in man. More recently, Eardley et al (14) and Cantor and co-workers (15,16) showed that in mice, the maintenance of immunological homeostasis was governed by the Qal feedback inhibitory circuit. These studies indicate that Lyl Qal+ cells induce Lyl, 2, 3, Qal+ cells to generate potent feedback inhibitory activity.…”

Section: Discussionmentioning

confidence: 99%

“…Functional studies demonstrate that removal of JRA+ cells with antibody and complement results in a three-to sixfold enhancement of immunoglobulin production in a pokeweed mitogen-driven system. Both the cellular expression ofantigen(s) defined by JRA autoantibody and augmentation of immunoglobulin synthesis suggests that JRA antisera might define the equivalent of a Qal-like antigen found on the inducer population for the suppression and/or feedback regulatory subset in man (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Autoantibody to an Immunoregulatory Inducer Population in Patients with Juvenile Rheumatoid Arthritis

Morimoto¹,

Reinherz²,

Borel³

et al. 1981

J. Clin. Invest.

109

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A B S T R A C T The human inducer (T4+) and reciprocal cytotoxic/suppressor (T5+/T8+) subsets have been defined by monoclonal antibodies. In the present study, we examined the relationship of naturally occurringanti-T cell autoantibodies found in patients with active juvenile rheumatoid arthritis (JRA) to these subsets. In one approach, normal T cells were treated with anti-T4 or anti-T8 to eliminate the corresponding subset of cells and then analyzed for reactivity with JRA sera. It was found that JRA sera were reactive with only 15% of an enriched cytotoxic/suppressor population, whereas they reacted with 37% of an enriched inducer population. In reciprocal studies, JRA+ T cells were eliminated with JRA sera and complement and the residual T cells (JRA-) reacted with monoclonal antibodies and indirect immunofluorescence on a fluorescence-activated cell sorter. As expected, the JRA sera and complement treatment of unfractionated T cells markedly diminished the T4+ subset, whereas there was a concomitant increase in T cells reactive with anti-T5 and anti-T8. A similar diminution in T4+ T cells was found in the circulating peripheral T cell compartment of patients with active JRA who possessed the JRA antibody.Functional studies demonstrated that removal of the JRA+ population of T cells diminished phytohemagglutinin and soluble antigen proliferative responses,

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“…The augmented primary immune response observed in the present study could have resulted from a defect in antigen nonspecific suppression, such as a defect in Ly-1+2+3 + feedback suppression (5,6). Perhaps the relatively normal secondary NZB CTL responses observed herein, reflect normal antigen-specific regulatory mechanisms.…”

Section: Discussionmentioning

confidence: 63%

NZB cytotoxic lymphocyte responses. Kinetic analyses.

Huston¹,

Steinberg

1980

The Journal of Experimental Medicine

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Recently, we have been studying the regulation of cytotoxic lymphocyte (CTL) responses in NZB mice. These studies have demonstrated that NZB CTL were relatively resistant to suppressor signals (1). In the present paper, we studied the timecourse of generation and the kinetics of lysis of CTL from nonprimed BALB/c, DBA/ 2, NZB, and alloantigen-primed BALB/c and NZB spleen cells in allogeneic mixed leukocyte cultures. These investigations suggested that NZB spleen cells have an accelerated generation of primary CTL responses, which, in some respects, mimic secondary CTL responses of alloantigen-primed mice. These observations shed light on recent reports of abnormal recognition phenomena by NZB T cells (2-4). Materials and MethodsMice. Alloantigen Sensitization In Vivo. Mice were sensitized by injection of 1 × 107 B6 spleen cells, in 0.05 ml of Hanks' balanced salt solution (HBSS), into each hind footpad. After 14 d, sensitized mice were sacrificed by cervical dislocation, and their spleens were removed under aseptic conditions. Single spleen-cell suspensions were prepared by gentle teasing in HBSS. The spleen cells were either assayed for CTL activity or were used as primed responder cells in in vitro mixed leukocyte cultures (MLC). MLC.Single spleen-cell suspensions were prepared in HBSS from in vivo primed mice and from nonprimed mice. B6 spleen cells, to be used as in vitro stimulator cells, were exposed to 1,500 rad of gamma irradiation. Cells were cultured in modified Eagle's minimum essential medium (MEM) with 10% heat-inactivated, mycoplasma-screened fetal calf serum (FCS) (Grand Island Biological Co., Grand Island, N. Y.), in 16-mm, flat-bottom culture wells (Cost ar, Data Packaging,, Cambridge, Mass.). 6-24 replicate wells that contained 1 × 107 responder cells and 1 X 10 irradiated stimulator cells were cultured in a final vol of 1.5 ml. Cultures were incubated for the specified number of days in a humidified atmosphere of 10% CO2, 7% 02, and 83% N2 at 37°C.Preparation of Target Cells. EL-4 tumor cells were maintained by weekly intraperitoneal 7 passage in B6 female mice. 2 × i0 tumor cells were incubated with 100 #Ci of 51Cr (Na2[ Cr]Oa, 200-500 Ci/g Cr sp act; New England Nuclear, Boston, Mass.) in 1 ml of HBSS with 10% FCS for 30 min at 37°C. The labeled target cells were then washed three times through 2 ml of FCS at 250 g for 10 rain and diluted in MEM with 10% FCS to the desired concentration.Cell-mediated Lympholysis Assay. Cytotoxicity was assayed as previously described (1). Effector cells were washed and resuspended in MEM with 10% FCS to the desired concentration of viable cells, and mixed with equal volumes (0.1 ml) of 51Cr-labeled target cells in serologic tubes. Effector and target cells were incubated for indicated times up to 4 h at 37°C in a humidified atmosphere with 5% CO2; radioactivity released into the supernate was measured 748

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Immunoregulatory circuits among T-cell sets. I. T-helper cells induce other T-cell sets to exert feedback inhibition.

Cited by 375 publications

References 14 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

Autoantibody to an Immunoregulatory Inducer Population in Patients with Juvenile Rheumatoid Arthritis

NZB cytotoxic lymphocyte responses. Kinetic analyses.

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