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CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity.

Kurts C, Carbone FR, Barnden M, Blanas E, Allison J, Heath WR, Miller JF - J. Exp. Med. (1997)

Bottom Line: Such cross-presentation of self-antigens leads to CD8+ T cell tolerance induction via deletion.Analysis of the fate of CD8+ T cells indicated that CD4(+) T cell help impaired their deletion.These data indicate that control of such help is critical for the maintenance of CD8+ T cell tolerance induced by cross-presentation.

View Article: PubMed Central - PubMed

Affiliation: Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.

ABSTRACT
Self-antigens expressed in extrathymic tissues such as the pancreas can be transported to draining lymph nodes and presented in a class I-restricted manner by bone marrow-derived antigen-presenting cells. Such cross-presentation of self-antigens leads to CD8+ T cell tolerance induction via deletion. In this report, we investigate the influence of CD4+ T cell help on this process. Small numbers of autoreactive OVA-specific CD8+ T cells were unable to cause diabetes when adoptively transferred into mice expressing ovalbumin in the pancreatic beta cells. Coinjection of OVA-specific CD4+ helper T cells, however, led to diabetes in a large proportion of mice (68%), suggesting that provision of help favored induction of autoimmunity. Analysis of the fate of CD8+ T cells indicated that CD4(+) T cell help impaired their deletion. These data indicate that control of such help is critical for the maintenance of CD8+ T cell tolerance induced by cross-presentation.

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Related in: MedlinePlus

OT-II cells do not enhance proliferation of OT-I cells in the  draining LNs. 2 × 106 CFSE-labeled OT-I cells were adoptively transferred into littermate RIP-mOVA mice alone (A and B) or together with  2.5 × 106 OT-II cells (C and D). After 52 h, lymphocytes from the renal  (A and C) and inguinal (B and D) LNs were analyzed by flow cytometry.  Profiles were gated on CFSE+ CD8+ cells. The numbers indicate the percentage of OT-I cells that had proliferated in vivo. These results are representative of five experiments.
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Figure 2: OT-II cells do not enhance proliferation of OT-I cells in the draining LNs. 2 × 106 CFSE-labeled OT-I cells were adoptively transferred into littermate RIP-mOVA mice alone (A and B) or together with 2.5 × 106 OT-II cells (C and D). After 52 h, lymphocytes from the renal (A and C) and inguinal (B and D) LNs were analyzed by flow cytometry. Profiles were gated on CFSE+ CD8+ cells. The numbers indicate the percentage of OT-I cells that had proliferated in vivo. These results are representative of five experiments.

Mentions: We then investigated whether OT-II cells achieved this effect by increasing the initial expansion of OT-I cells, or by impairing their deletion. To examine the first possibility, CFSE-labeled OT-I cells were adoptively transferred into RIP-mOVA mice in the presence or absence of coinjected OT-II cells. This technique enables monitoring of proliferation by detecting cells with 2n-fold reduced fluorescence intensity, where n is the number of cell cycles (5, 19). 2 d after adoptive transfer, we compared the CFSE fluorescence profiles of OT-I cells from the draining LNs of the kidney (Fig. 2) or pancreas (data not shown). 2 × 106 OT-II cells did not cause an obvious change in the proliferative peaks in these sites. No changes were observed with smaller numbers of CFSE-labeled OT-I cells (0.5 × 106), or at later time points (data not shown). These results suggested that the rate of OT-I cell cycling was not affected by OT-II cell help.


CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity.

Kurts C, Carbone FR, Barnden M, Blanas E, Allison J, Heath WR, Miller JF - J. Exp. Med. (1997)

OT-II cells do not enhance proliferation of OT-I cells in the  draining LNs. 2 × 106 CFSE-labeled OT-I cells were adoptively transferred into littermate RIP-mOVA mice alone (A and B) or together with  2.5 × 106 OT-II cells (C and D). After 52 h, lymphocytes from the renal  (A and C) and inguinal (B and D) LNs were analyzed by flow cytometry.  Profiles were gated on CFSE+ CD8+ cells. The numbers indicate the percentage of OT-I cells that had proliferated in vivo. These results are representative of five experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199175&req=5

Figure 2: OT-II cells do not enhance proliferation of OT-I cells in the draining LNs. 2 × 106 CFSE-labeled OT-I cells were adoptively transferred into littermate RIP-mOVA mice alone (A and B) or together with 2.5 × 106 OT-II cells (C and D). After 52 h, lymphocytes from the renal (A and C) and inguinal (B and D) LNs were analyzed by flow cytometry. Profiles were gated on CFSE+ CD8+ cells. The numbers indicate the percentage of OT-I cells that had proliferated in vivo. These results are representative of five experiments.
Mentions: We then investigated whether OT-II cells achieved this effect by increasing the initial expansion of OT-I cells, or by impairing their deletion. To examine the first possibility, CFSE-labeled OT-I cells were adoptively transferred into RIP-mOVA mice in the presence or absence of coinjected OT-II cells. This technique enables monitoring of proliferation by detecting cells with 2n-fold reduced fluorescence intensity, where n is the number of cell cycles (5, 19). 2 d after adoptive transfer, we compared the CFSE fluorescence profiles of OT-I cells from the draining LNs of the kidney (Fig. 2) or pancreas (data not shown). 2 × 106 OT-II cells did not cause an obvious change in the proliferative peaks in these sites. No changes were observed with smaller numbers of CFSE-labeled OT-I cells (0.5 × 106), or at later time points (data not shown). These results suggested that the rate of OT-I cell cycling was not affected by OT-II cell help.

Bottom Line: Such cross-presentation of self-antigens leads to CD8+ T cell tolerance induction via deletion.Analysis of the fate of CD8+ T cells indicated that CD4(+) T cell help impaired their deletion.These data indicate that control of such help is critical for the maintenance of CD8+ T cell tolerance induced by cross-presentation.

View Article: PubMed Central - PubMed

Affiliation: Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.

ABSTRACT
Self-antigens expressed in extrathymic tissues such as the pancreas can be transported to draining lymph nodes and presented in a class I-restricted manner by bone marrow-derived antigen-presenting cells. Such cross-presentation of self-antigens leads to CD8+ T cell tolerance induction via deletion. In this report, we investigate the influence of CD4+ T cell help on this process. Small numbers of autoreactive OVA-specific CD8+ T cells were unable to cause diabetes when adoptively transferred into mice expressing ovalbumin in the pancreatic beta cells. Coinjection of OVA-specific CD4+ helper T cells, however, led to diabetes in a large proportion of mice (68%), suggesting that provision of help favored induction of autoimmunity. Analysis of the fate of CD8+ T cells indicated that CD4(+) T cell help impaired their deletion. These data indicate that control of such help is critical for the maintenance of CD8+ T cell tolerance induced by cross-presentation.

Show MeSH
Related in: MedlinePlus