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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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Related in: MedlinePlus

Disappearance of OT-I cells in TG-RIP mice after removal  of their thymus graft. Thymus graft was removed from TG-RIP mice and  TG-nontransgenic controls 3 mo after implantation. The proportion of  CD8+ peripheral blood cells that were Vα2+Vβ5+ was then determined  by flow cytometry on days 2, 11, 18, and 35 after thymectomy. The proportion found at day 2 after removal of the thymus grafts was considered  100% in this particular mouse, and the following values were given as a  percent of this starting value. TG-RIP, not operated (○); TG-RIP, thymus graft removed (▿); TG-RIP, thymus graft and left kidney removed  (▵); TG-nontransgenic littermate, not operated (□); TG-nontransgenic  littermate, thymus graft removed (⋄).
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Figure 6: Disappearance of OT-I cells in TG-RIP mice after removal of their thymus graft. Thymus graft was removed from TG-RIP mice and TG-nontransgenic controls 3 mo after implantation. The proportion of CD8+ peripheral blood cells that were Vα2+Vβ5+ was then determined by flow cytometry on days 2, 11, 18, and 35 after thymectomy. The proportion found at day 2 after removal of the thymus grafts was considered 100% in this particular mouse, and the following values were given as a percent of this starting value. TG-RIP, not operated (○); TG-RIP, thymus graft removed (▿); TG-RIP, thymus graft and left kidney removed (▵); TG-nontransgenic littermate, not operated (□); TG-nontransgenic littermate, thymus graft removed (⋄).

Mentions: To determine the fate of those few activated OT-I cells remaining in the periphery of TG-RIP mice, the thymus grafts were removed 3 mo after implantation to stop further T cell production. The proportion of OT-I cells was then examined in the blood at various later timepoints. This revealed a continuous decline in the proportion of OT-I cells in TG-RIP mice (Fig. 6), consistent with the idea that a continuous deletion process was in operation. These few remaining cells were also able to proliferate upon restimulation with antigen in vivo (data not shown).


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)

Disappearance of OT-I cells in TG-RIP mice after removal  of their thymus graft. Thymus graft was removed from TG-RIP mice and  TG-nontransgenic controls 3 mo after implantation. The proportion of  CD8+ peripheral blood cells that were Vα2+Vβ5+ was then determined  by flow cytometry on days 2, 11, 18, and 35 after thymectomy. The proportion found at day 2 after removal of the thymus grafts was considered  100% in this particular mouse, and the following values were given as a  percent of this starting value. TG-RIP, not operated (○); TG-RIP, thymus graft removed (▿); TG-RIP, thymus graft and left kidney removed  (▵); TG-nontransgenic littermate, not operated (□); TG-nontransgenic  littermate, thymus graft removed (⋄).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2198972&req=5

Figure 6: Disappearance of OT-I cells in TG-RIP mice after removal of their thymus graft. Thymus graft was removed from TG-RIP mice and TG-nontransgenic controls 3 mo after implantation. The proportion of CD8+ peripheral blood cells that were Vα2+Vβ5+ was then determined by flow cytometry on days 2, 11, 18, and 35 after thymectomy. The proportion found at day 2 after removal of the thymus grafts was considered 100% in this particular mouse, and the following values were given as a percent of this starting value. TG-RIP, not operated (○); TG-RIP, thymus graft removed (▿); TG-RIP, thymus graft and left kidney removed (▵); TG-nontransgenic littermate, not operated (□); TG-nontransgenic littermate, thymus graft removed (⋄).
Mentions: To determine the fate of those few activated OT-I cells remaining in the periphery of TG-RIP mice, the thymus grafts were removed 3 mo after implantation to stop further T cell production. The proportion of OT-I cells was then examined in the blood at various later timepoints. This revealed a continuous decline in the proportion of OT-I cells in TG-RIP mice (Fig. 6), consistent with the idea that a continuous deletion process was in operation. These few remaining cells were also able to proliferate upon restimulation with antigen in vivo (data not shown).

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