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Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells.

Kurts C, Kosaka H, Carbone FR, Miller JF, Heath WR - J. Exp. Med. (1997)

Bottom Line: Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes.Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances.Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.

View Article: PubMed Central - PubMed

Affiliation: Thymus Biology Unit, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville 3050, Victoria, Australia.

ABSTRACT
In this report, we show that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8(+) T cells. We had previously shown that transfer of ovalbumin (OVA)-specific CD8(+) T cells (OT-I cells) into rat insulin promoter-membrane-bound form of OVA transgenic mice, which express the model autoantigen OVA in the proximal tubular cells of the kidneys, the beta cells of the pancreas, the thymus, and the testis of male mice, led to the activation of OT-I cells in the draining lymph nodes. This was due to class I-restricted cross-presentation of exogenous OVA on a bone marrow-derived antigen presenting cell (APC) population. Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes. Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances. Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.

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OT-I cells are deleted in response to recognition of antigen  on cross-presenting APC. Bone marrow from B6 mice was grafted into  RIP–mOVA.bm1 mice and nontransgenic littermates. 14 wk later, 6 ×  106 OT-I cells were adoptively transferred, and after 8 wk the number of  Vα2+Vβ5+CD8+ cells in the LN and spleen of the recipients was determined by flow cytometry. The proportion of Vα2+Vβ5+ cells in the  CD8+ population was 7.5–10% in nontransgenic, and 1.4–3.5% in transgenic recipients. An average of 1.4% of CD8+ cells were Vα2+Vβ5+ in  uninjected mice. To derive the total number of OT-I cells, this 1.4% was  subtracted from the proportion of Vα2+Vβ5+ cells in the CD8+ cells in  experimental mice and the difference was multiplied with the proportion  of CD8+ T cells in the live cells and with the number of live cells. These  results are representative for two such experiments consisting of four mice  per group.
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Figure 3: OT-I cells are deleted in response to recognition of antigen on cross-presenting APC. Bone marrow from B6 mice was grafted into RIP–mOVA.bm1 mice and nontransgenic littermates. 14 wk later, 6 × 106 OT-I cells were adoptively transferred, and after 8 wk the number of Vα2+Vβ5+CD8+ cells in the LN and spleen of the recipients was determined by flow cytometry. The proportion of Vα2+Vβ5+ cells in the CD8+ population was 7.5–10% in nontransgenic, and 1.4–3.5% in transgenic recipients. An average of 1.4% of CD8+ cells were Vα2+Vβ5+ in uninjected mice. To derive the total number of OT-I cells, this 1.4% was subtracted from the proportion of Vα2+Vβ5+ cells in the CD8+ cells in experimental mice and the difference was multiplied with the proportion of CD8+ T cells in the live cells and with the number of live cells. These results are representative for two such experiments consisting of four mice per group.

Mentions: The above results indicate that a bone marrow–derived APC was capable of processing and presenting antigens expressed by peripheral tissues for activation of autoreactive CD8+ T cells. To determine how the immune system normally copes with such autoreactive cells, we examined the ultimate fate of these cells. To detect adoptively transferred OT-I cells in unirradiated recipients several weeks after transfer, it was necessary to inject at least 5 × 106 cells. However, under these circumstances OT-I cells infiltrated the pancreatic islets after day 3, and caused diabetes in 100% of 16 RIP–mOVA mice by day 9 (data not shown). Smaller numbers of cells, e.g., 0.25 × 106 cells, did not cause diabetes in 25 recipients, but detection of these few cells was not possible several weeks after transfer, even in nontransgenic controls. Presumably, OT-I cells were activated after transfer in both cases, but only the larger dose caused sufficient destruction to result in diabetes. To avoid the problem of β cell destruction, we transferred 6 × 106 OT-I cells into B6→ RIP–mOVA.bm1 chimeric mice, in which OT-I cells could recognize antigen on the cross-presenting bone marrow–derived APCs, but could not interact with OVA-expressing peripheral tissues of the bm1 haplotype. After 8 wk, far fewer OT-I cells were recovered from the lymphatic tissues of B6→ RIP– mOVA.bm1 mice than from nontransgenic B6→ bm1 mice (Fig. 3). These data suggest that OT-I cells were deleted after recognizing exogenously processed OVA on bone marrow–derived APC in the draining lymph nodes of OVA-expressing tissue.


Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells.

Kurts C, Kosaka H, Carbone FR, Miller JF, Heath WR - J. Exp. Med. (1997)

OT-I cells are deleted in response to recognition of antigen  on cross-presenting APC. Bone marrow from B6 mice was grafted into  RIP–mOVA.bm1 mice and nontransgenic littermates. 14 wk later, 6 ×  106 OT-I cells were adoptively transferred, and after 8 wk the number of  Vα2+Vβ5+CD8+ cells in the LN and spleen of the recipients was determined by flow cytometry. The proportion of Vα2+Vβ5+ cells in the  CD8+ population was 7.5–10% in nontransgenic, and 1.4–3.5% in transgenic recipients. An average of 1.4% of CD8+ cells were Vα2+Vβ5+ in  uninjected mice. To derive the total number of OT-I cells, this 1.4% was  subtracted from the proportion of Vα2+Vβ5+ cells in the CD8+ cells in  experimental mice and the difference was multiplied with the proportion  of CD8+ T cells in the live cells and with the number of live cells. These  results are representative for two such experiments consisting of four mice  per group.
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Related In: Results  -  Collection

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Figure 3: OT-I cells are deleted in response to recognition of antigen on cross-presenting APC. Bone marrow from B6 mice was grafted into RIP–mOVA.bm1 mice and nontransgenic littermates. 14 wk later, 6 × 106 OT-I cells were adoptively transferred, and after 8 wk the number of Vα2+Vβ5+CD8+ cells in the LN and spleen of the recipients was determined by flow cytometry. The proportion of Vα2+Vβ5+ cells in the CD8+ population was 7.5–10% in nontransgenic, and 1.4–3.5% in transgenic recipients. An average of 1.4% of CD8+ cells were Vα2+Vβ5+ in uninjected mice. To derive the total number of OT-I cells, this 1.4% was subtracted from the proportion of Vα2+Vβ5+ cells in the CD8+ cells in experimental mice and the difference was multiplied with the proportion of CD8+ T cells in the live cells and with the number of live cells. These results are representative for two such experiments consisting of four mice per group.
Mentions: The above results indicate that a bone marrow–derived APC was capable of processing and presenting antigens expressed by peripheral tissues for activation of autoreactive CD8+ T cells. To determine how the immune system normally copes with such autoreactive cells, we examined the ultimate fate of these cells. To detect adoptively transferred OT-I cells in unirradiated recipients several weeks after transfer, it was necessary to inject at least 5 × 106 cells. However, under these circumstances OT-I cells infiltrated the pancreatic islets after day 3, and caused diabetes in 100% of 16 RIP–mOVA mice by day 9 (data not shown). Smaller numbers of cells, e.g., 0.25 × 106 cells, did not cause diabetes in 25 recipients, but detection of these few cells was not possible several weeks after transfer, even in nontransgenic controls. Presumably, OT-I cells were activated after transfer in both cases, but only the larger dose caused sufficient destruction to result in diabetes. To avoid the problem of β cell destruction, we transferred 6 × 106 OT-I cells into B6→ RIP–mOVA.bm1 chimeric mice, in which OT-I cells could recognize antigen on the cross-presenting bone marrow–derived APCs, but could not interact with OVA-expressing peripheral tissues of the bm1 haplotype. After 8 wk, far fewer OT-I cells were recovered from the lymphatic tissues of B6→ RIP– mOVA.bm1 mice than from nontransgenic B6→ bm1 mice (Fig. 3). These data suggest that OT-I cells were deleted after recognizing exogenously processed OVA on bone marrow–derived APC in the draining lymph nodes of OVA-expressing tissue.

Bottom Line: Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes.Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances.Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.

View Article: PubMed Central - PubMed

Affiliation: Thymus Biology Unit, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville 3050, Victoria, Australia.

ABSTRACT
In this report, we show that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8(+) T cells. We had previously shown that transfer of ovalbumin (OVA)-specific CD8(+) T cells (OT-I cells) into rat insulin promoter-membrane-bound form of OVA transgenic mice, which express the model autoantigen OVA in the proximal tubular cells of the kidneys, the beta cells of the pancreas, the thymus, and the testis of male mice, led to the activation of OT-I cells in the draining lymph nodes. This was due to class I-restricted cross-presentation of exogenous OVA on a bone marrow-derived antigen presenting cell (APC) population. Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes. Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances. Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.

Show MeSH
Related in: MedlinePlus