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Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo.

Reed JR, Vukmanovic-Stejic M, Fletcher JM, Soares MV, Cook JE, Orteu CH, Jackson SE, Birch KE, Foster GR, Salmon M, Beverley PC, Rustin MH, Akbar AN - J. Exp. Med. (2004)

Bottom Line: Furthermore, significant telomere erosion occurred in specific T cells that respond in the skin, but not in those that are found in the blood from the same individuals.Antibody inhibition studies indicated that type I interferon (IFN), which was identified at high levels in the tissue fluid and by immunohistology, was responsible in part for the telomerase inhibition.Furthermore, the addition of IFN-alpha to PPD-stimulated CD4+ T cells directly inhibited telomerase activity in vitro.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Immunology and Molecular Pathology, Div. of Infection and Immunity, University College London, 46 Cleveland St., London W1T 4JF, England, UK.

ABSTRACT
The extent of human memory T cell proliferation, differentiation, and telomere erosion that occurs after a single episode of immune challenge in vivo is unclear. To investigate this, we injected tuberculin purified protein derivative (PPD) into the skin of immune individuals and isolated responsive T cells from the site of antigenic challenge at different times. PPD-specific CD4+ T cells proliferated and differentiated extensively in the skin during this secondary response. Furthermore, significant telomere erosion occurred in specific T cells that respond in the skin, but not in those that are found in the blood from the same individuals. Tissue fluid obtained from the site of PPD challenge in the skin inhibited the induction of the enzyme telomerase in T cells in vitro. Antibody inhibition studies indicated that type I interferon (IFN), which was identified at high levels in the tissue fluid and by immunohistology, was responsible in part for the telomerase inhibition. Furthermore, the addition of IFN-alpha to PPD-stimulated CD4+ T cells directly inhibited telomerase activity in vitro. Therefore, these results suggest that the rate of telomere erosion in proliferating, antigen-specific CD4+ T cells may be accelerated by type I IFN during a secondary response in vivo.

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The Mantoux test (MT): a human in vivo model of a memory immune response. Samples were collected between 0 and 19 d after PPD injection (a, left). Skin biopsies were collected for immunohistochemistry, and the top right panel shows a day-3 MT skin section with a perivascular (PV) collection of CD3+ T cells (E and D denote the epidermis and dermis, respectively; magnification, 20). Cutaneous lymphocytes were isolated from skin SBs that were induced over the sites of PPD injection at different times (a, bottom right). In panel b, the clinical score resulting from PPD challenge was measured at the time of sampling (□, left y axis), whereas the number of T cells within dermal perivascular infiltrates was determined by indirect immunoperoxidase staining (▪, right y axis). The mean ± SEM of five experiments per time point is shown. In panel c, the percentage of granulocytes (black bars), lymphocytes (gray bars), and other leukocytes (white bars) isolated from SBs raised at different time points after PPD injection is shown. Leukocyte proportions were determined by flow cytometry. The mean ± SEM for three to six experiments per time point is shown. The percentage of CD3+ T cells expressing CD4 in the peripheral blood (black bars) and blisters (white bars) during the course of the MT response was determined by flow cytometry (d). The mean ± SEM for four to seven experiments per time point is shown.
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fig1: The Mantoux test (MT): a human in vivo model of a memory immune response. Samples were collected between 0 and 19 d after PPD injection (a, left). Skin biopsies were collected for immunohistochemistry, and the top right panel shows a day-3 MT skin section with a perivascular (PV) collection of CD3+ T cells (E and D denote the epidermis and dermis, respectively; magnification, 20). Cutaneous lymphocytes were isolated from skin SBs that were induced over the sites of PPD injection at different times (a, bottom right). In panel b, the clinical score resulting from PPD challenge was measured at the time of sampling (□, left y axis), whereas the number of T cells within dermal perivascular infiltrates was determined by indirect immunoperoxidase staining (▪, right y axis). The mean ± SEM of five experiments per time point is shown. In panel c, the percentage of granulocytes (black bars), lymphocytes (gray bars), and other leukocytes (white bars) isolated from SBs raised at different time points after PPD injection is shown. Leukocyte proportions were determined by flow cytometry. The mean ± SEM for three to six experiments per time point is shown. The percentage of CD3+ T cells expressing CD4 in the peripheral blood (black bars) and blisters (white bars) during the course of the MT response was determined by flow cytometry (d). The mean ± SEM for four to seven experiments per time point is shown.

Mentions: Healthy individuals who had been vaccinated previously against tuberculosis with BCG were selected for this analysis. The MT was induced by the intradermal injection of tuberculin PPD (Fig. 1 a). The clinical manifestation of this response was measured in terms of the change in erythema, size of induration, and palpability of the lesion, which peaked at 3 d after PPD injection, confirming previous papers (Fig. 1 b and references 5, 20). A novel observation was that the number of infiltrating T cells did not reach maximal levels until 7 d after PPD injection (Fig. 1 b). Therefore, the clinical and cellular peaks of this secondary response are asynchronous.


Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo.

Reed JR, Vukmanovic-Stejic M, Fletcher JM, Soares MV, Cook JE, Orteu CH, Jackson SE, Birch KE, Foster GR, Salmon M, Beverley PC, Rustin MH, Akbar AN - J. Exp. Med. (2004)

The Mantoux test (MT): a human in vivo model of a memory immune response. Samples were collected between 0 and 19 d after PPD injection (a, left). Skin biopsies were collected for immunohistochemistry, and the top right panel shows a day-3 MT skin section with a perivascular (PV) collection of CD3+ T cells (E and D denote the epidermis and dermis, respectively; magnification, 20). Cutaneous lymphocytes were isolated from skin SBs that were induced over the sites of PPD injection at different times (a, bottom right). In panel b, the clinical score resulting from PPD challenge was measured at the time of sampling (□, left y axis), whereas the number of T cells within dermal perivascular infiltrates was determined by indirect immunoperoxidase staining (▪, right y axis). The mean ± SEM of five experiments per time point is shown. In panel c, the percentage of granulocytes (black bars), lymphocytes (gray bars), and other leukocytes (white bars) isolated from SBs raised at different time points after PPD injection is shown. Leukocyte proportions were determined by flow cytometry. The mean ± SEM for three to six experiments per time point is shown. The percentage of CD3+ T cells expressing CD4 in the peripheral blood (black bars) and blisters (white bars) during the course of the MT response was determined by flow cytometry (d). The mean ± SEM for four to seven experiments per time point is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211820&req=5

fig1: The Mantoux test (MT): a human in vivo model of a memory immune response. Samples were collected between 0 and 19 d after PPD injection (a, left). Skin biopsies were collected for immunohistochemistry, and the top right panel shows a day-3 MT skin section with a perivascular (PV) collection of CD3+ T cells (E and D denote the epidermis and dermis, respectively; magnification, 20). Cutaneous lymphocytes were isolated from skin SBs that were induced over the sites of PPD injection at different times (a, bottom right). In panel b, the clinical score resulting from PPD challenge was measured at the time of sampling (□, left y axis), whereas the number of T cells within dermal perivascular infiltrates was determined by indirect immunoperoxidase staining (▪, right y axis). The mean ± SEM of five experiments per time point is shown. In panel c, the percentage of granulocytes (black bars), lymphocytes (gray bars), and other leukocytes (white bars) isolated from SBs raised at different time points after PPD injection is shown. Leukocyte proportions were determined by flow cytometry. The mean ± SEM for three to six experiments per time point is shown. The percentage of CD3+ T cells expressing CD4 in the peripheral blood (black bars) and blisters (white bars) during the course of the MT response was determined by flow cytometry (d). The mean ± SEM for four to seven experiments per time point is shown.
Mentions: Healthy individuals who had been vaccinated previously against tuberculosis with BCG were selected for this analysis. The MT was induced by the intradermal injection of tuberculin PPD (Fig. 1 a). The clinical manifestation of this response was measured in terms of the change in erythema, size of induration, and palpability of the lesion, which peaked at 3 d after PPD injection, confirming previous papers (Fig. 1 b and references 5, 20). A novel observation was that the number of infiltrating T cells did not reach maximal levels until 7 d after PPD injection (Fig. 1 b). Therefore, the clinical and cellular peaks of this secondary response are asynchronous.

Bottom Line: Furthermore, significant telomere erosion occurred in specific T cells that respond in the skin, but not in those that are found in the blood from the same individuals.Antibody inhibition studies indicated that type I interferon (IFN), which was identified at high levels in the tissue fluid and by immunohistology, was responsible in part for the telomerase inhibition.Furthermore, the addition of IFN-alpha to PPD-stimulated CD4+ T cells directly inhibited telomerase activity in vitro.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Immunology and Molecular Pathology, Div. of Infection and Immunity, University College London, 46 Cleveland St., London W1T 4JF, England, UK.

ABSTRACT
The extent of human memory T cell proliferation, differentiation, and telomere erosion that occurs after a single episode of immune challenge in vivo is unclear. To investigate this, we injected tuberculin purified protein derivative (PPD) into the skin of immune individuals and isolated responsive T cells from the site of antigenic challenge at different times. PPD-specific CD4+ T cells proliferated and differentiated extensively in the skin during this secondary response. Furthermore, significant telomere erosion occurred in specific T cells that respond in the skin, but not in those that are found in the blood from the same individuals. Tissue fluid obtained from the site of PPD challenge in the skin inhibited the induction of the enzyme telomerase in T cells in vitro. Antibody inhibition studies indicated that type I interferon (IFN), which was identified at high levels in the tissue fluid and by immunohistology, was responsible in part for the telomerase inhibition. Furthermore, the addition of IFN-alpha to PPD-stimulated CD4+ T cells directly inhibited telomerase activity in vitro. Therefore, these results suggest that the rate of telomere erosion in proliferating, antigen-specific CD4+ T cells may be accelerated by type I IFN during a secondary response in vivo.

Show MeSH
Related in: MedlinePlus