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Anergy in peripheral memory CD4(+) T cells induced by low avidity engagement of T cell receptor.

Mirshahidi S, Huang CT, Sadegh-Nasseri S - J. Exp. Med. (2001)

Bottom Line: We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression.Anergy is the most likely mechanism because addition of interleukin 2-reversed anergy in specific T cells.Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti-CTLA-4 blocking antibody restored anergy in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.

ABSTRACT
Induction of tolerance in self-reactive memory T cells is an important process in the prevention of autoimmune responses against peripheral self-antigens in autoimmune diseases. Although naive T cells can readily be tolerized, memory T cells are less susceptible to tolerance induction. Recently, we demonstrated that low avidity engagement of T cell receptor (TCR) by low densities of agonist peptides induced anergy in T cell clones. Since memory T cells are more responsive to lower antigenic stimulation, we hypothesized that a low avidity TCR engagement may induce tolerance in memory T cells. We have explored two antigenic systems in two transgenic mouse models, and have tracked specific T cells that are primed and show memory phenotype. We demonstrate that memory CD4(+) T cells can be rendered anergic by presentation of low densities of agonist peptide-major histocompatibility complex complexes in vivo. We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression. Anergy is the most likely mechanism because addition of interleukin 2-reversed anergy in specific T cells. Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti-CTLA-4 blocking antibody restored anergy in vivo.

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Expression of CTLA-4 on cells exhibiting anergy. Surface expression of CTLA-4 on (A) clonotypic HA-specific CD4 cells from draining lymph nodes of adoptively transferred mice 48 h after the tolerogenic peptide administration and (B) HA306–318–specific CD4+ T cells from HLA-DR1 mice 8 d after in vitro culture in presence of peptide as examined by anti–CTLA-4 antibody staining. Results are from one out of two independent experiments.
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Figure 7: Expression of CTLA-4 on cells exhibiting anergy. Surface expression of CTLA-4 on (A) clonotypic HA-specific CD4 cells from draining lymph nodes of adoptively transferred mice 48 h after the tolerogenic peptide administration and (B) HA306–318–specific CD4+ T cells from HLA-DR1 mice 8 d after in vitro culture in presence of peptide as examined by anti–CTLA-4 antibody staining. Results are from one out of two independent experiments.

Mentions: A critical role for CTLA-4 in negative regulation of the immune response has been established by the findings that CTLA-4–deficient (CTLA−/−) mice display a severe lymphoproliferative disorder combined with massive lymphocytic infiltration that leads to tissue destruction and death of the mice at 3–4 wk of age 3132. T cell tolerance in vivo may arise from dominant engagement of B7 molecules by the CTLA-4 over CD28 and not from lack of costimulation 33. To test possible involvement of CTLA-4 we measured levels of CTLA-4 expression in clonotypic HA-specific CD4+ T cells (6.5+, CD4+) of draining lymph nodes 2 d after the second peptide injections 3435, and in HA306–318–specific CD4+ T cells from HLA-DR1 mice, 8 d after in vitro culture in the presence of peptide. Interestingly, we observed a direct correlation between the levels of CTLA-4 expression and the induction of T cell unresponsiveness (Fig. 7a and Fig. b). Mice exposed to tolerogenic dose of peptide expressed an increased level of CTLA-4 on their T cells, whereas T cells from mock-immunized mice and those injected with no peptide or an immunogenic dose had comparable levels of CTLA-4. These observations suggest that tolerance induced by low densities of agonist peptide in vivo may occur through CTLA-4 signaling.


Anergy in peripheral memory CD4(+) T cells induced by low avidity engagement of T cell receptor.

Mirshahidi S, Huang CT, Sadegh-Nasseri S - J. Exp. Med. (2001)

Expression of CTLA-4 on cells exhibiting anergy. Surface expression of CTLA-4 on (A) clonotypic HA-specific CD4 cells from draining lymph nodes of adoptively transferred mice 48 h after the tolerogenic peptide administration and (B) HA306–318–specific CD4+ T cells from HLA-DR1 mice 8 d after in vitro culture in presence of peptide as examined by anti–CTLA-4 antibody staining. Results are from one out of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195956&req=5

Figure 7: Expression of CTLA-4 on cells exhibiting anergy. Surface expression of CTLA-4 on (A) clonotypic HA-specific CD4 cells from draining lymph nodes of adoptively transferred mice 48 h after the tolerogenic peptide administration and (B) HA306–318–specific CD4+ T cells from HLA-DR1 mice 8 d after in vitro culture in presence of peptide as examined by anti–CTLA-4 antibody staining. Results are from one out of two independent experiments.
Mentions: A critical role for CTLA-4 in negative regulation of the immune response has been established by the findings that CTLA-4–deficient (CTLA−/−) mice display a severe lymphoproliferative disorder combined with massive lymphocytic infiltration that leads to tissue destruction and death of the mice at 3–4 wk of age 3132. T cell tolerance in vivo may arise from dominant engagement of B7 molecules by the CTLA-4 over CD28 and not from lack of costimulation 33. To test possible involvement of CTLA-4 we measured levels of CTLA-4 expression in clonotypic HA-specific CD4+ T cells (6.5+, CD4+) of draining lymph nodes 2 d after the second peptide injections 3435, and in HA306–318–specific CD4+ T cells from HLA-DR1 mice, 8 d after in vitro culture in the presence of peptide. Interestingly, we observed a direct correlation between the levels of CTLA-4 expression and the induction of T cell unresponsiveness (Fig. 7a and Fig. b). Mice exposed to tolerogenic dose of peptide expressed an increased level of CTLA-4 on their T cells, whereas T cells from mock-immunized mice and those injected with no peptide or an immunogenic dose had comparable levels of CTLA-4. These observations suggest that tolerance induced by low densities of agonist peptide in vivo may occur through CTLA-4 signaling.

Bottom Line: We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression.Anergy is the most likely mechanism because addition of interleukin 2-reversed anergy in specific T cells.Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti-CTLA-4 blocking antibody restored anergy in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.

ABSTRACT
Induction of tolerance in self-reactive memory T cells is an important process in the prevention of autoimmune responses against peripheral self-antigens in autoimmune diseases. Although naive T cells can readily be tolerized, memory T cells are less susceptible to tolerance induction. Recently, we demonstrated that low avidity engagement of T cell receptor (TCR) by low densities of agonist peptides induced anergy in T cell clones. Since memory T cells are more responsive to lower antigenic stimulation, we hypothesized that a low avidity TCR engagement may induce tolerance in memory T cells. We have explored two antigenic systems in two transgenic mouse models, and have tracked specific T cells that are primed and show memory phenotype. We demonstrate that memory CD4(+) T cells can be rendered anergic by presentation of low densities of agonist peptide-major histocompatibility complex complexes in vivo. We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression. Anergy is the most likely mechanism because addition of interleukin 2-reversed anergy in specific T cells. Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti-CTLA-4 blocking antibody restored anergy in vivo.

Show MeSH
Related in: MedlinePlus