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Superantigens increase the survival of mice bearing T cell lymphomas by inducing apoptosis of neoplastic cells.

Mundiñano J, Berguer PM, Cabrera G, Lorenzo D, Nepomnaschy I, Piazzon I - PLoS ONE (2010)

Bottom Line: Superantigens bind to major histocompatibility complex class II molecules and interact with T cells expressing a particular T cell receptor Vβ inducing a strong proliferation/deletion response of the superantigen-reactive T cells.However, there have been no attempts to investigate the ability of Sags to induce apoptosis in neoplastic T cells by signaling through the Vβ region of their TCR.The possibility of a therapeutic use of superantigens in lymphoma/leukemia T cell malignancies is discussed.

View Article: PubMed Central - PubMed

Affiliation: ILEX-CONICET, División Medicina Experimental, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.

ABSTRACT
Superantigens bind to major histocompatibility complex class II molecules and interact with T cells expressing a particular T cell receptor Vβ inducing a strong proliferation/deletion response of the superantigen-reactive T cells. However, there have been no attempts to investigate the ability of Sags to induce apoptosis in neoplastic T cells by signaling through the Vβ region of their TCR. In the present study we show that bacterial and MMTV-encoded superantigens induce the apoptosis of AKR/J cognate lymphoma T cells both in vitro and in vivo. The Fas-Fas-L pathway was shown to be involved in the apoptosis of lymphoma T cells induced by bacterial superantigens. In vivo exposure to bacterial superantigens was able to improve the survival of lymphoma bearing mice. Moreover, the permanent expression of a retroviral encoded superantigen induced the complete remission of an aggressive lymphoma in a high percentage of mice. The possibility of a therapeutic use of superantigens in lymphoma/leukemia T cell malignancies is discussed.

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Sags induce increases in the proliferative levels of cognate lymphoma T cells.(A–B) Proliferative response of lymphoma T cells in vitro. (A) Different numbers of T14 lymphoma cells were co-cultured with 0.7×105 mitomycin C-pretreated splenocytes from (•) non-infected AKR/J mice, (▪) MMTV BALB2-infected AKR/J mice or (▴) MMTV BALB14-infected AKR/J mice. The proliferative response was assessed by 3H-thymidine incorporation during the last 18 hr of a 1-day culture period. Data are expressed as the mean ± SD, n = 5, **p<0.01. (B) Different numbers of T8.2 lymphoma cells were co-cultured with 0.7×105 mitomycin C-pretreated intraperitoneal macrophages in the presence of 10 µg/ml of (▪) SEI, (▴) SEB or (•) PBS. The proliferative response was assessed by 3H-thymidine incorporation during the last 18 hr of a 1-day culture period. Data are expressed as the mean ± SD, n = 5, **p<0.01. (C) Proliferative response of lymphoma T cells in vivo. CFSE-stained T5 lymphoma cells (5×106) were transferred intraperitoneally into syngeneic AKR/J mice. The mice were divided into three groups (n = 3 per group) and received an intraperitoneal injection of 25 µg of SEB, SEI or PBS. Twenty four hours later cells were collected by intraperitoneal washing and CFSE fluorescence was analyzed. Overlayed histograms depict a representative example. All the experiments were performed three times with similar results.
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pone-0015694-g002: Sags induce increases in the proliferative levels of cognate lymphoma T cells.(A–B) Proliferative response of lymphoma T cells in vitro. (A) Different numbers of T14 lymphoma cells were co-cultured with 0.7×105 mitomycin C-pretreated splenocytes from (•) non-infected AKR/J mice, (▪) MMTV BALB2-infected AKR/J mice or (▴) MMTV BALB14-infected AKR/J mice. The proliferative response was assessed by 3H-thymidine incorporation during the last 18 hr of a 1-day culture period. Data are expressed as the mean ± SD, n = 5, **p<0.01. (B) Different numbers of T8.2 lymphoma cells were co-cultured with 0.7×105 mitomycin C-pretreated intraperitoneal macrophages in the presence of 10 µg/ml of (▪) SEI, (▴) SEB or (•) PBS. The proliferative response was assessed by 3H-thymidine incorporation during the last 18 hr of a 1-day culture period. Data are expressed as the mean ± SD, n = 5, **p<0.01. (C) Proliferative response of lymphoma T cells in vivo. CFSE-stained T5 lymphoma cells (5×106) were transferred intraperitoneally into syngeneic AKR/J mice. The mice were divided into three groups (n = 3 per group) and received an intraperitoneal injection of 25 µg of SEB, SEI or PBS. Twenty four hours later cells were collected by intraperitoneal washing and CFSE fluorescence was analyzed. Overlayed histograms depict a representative example. All the experiments were performed three times with similar results.

Mentions: The ability of bacterial and viral Sags to increase the in vitro proliferation of cognate lymphoma T cells was first investigated. T8 and T8.2 (Vβ8.1,8.2+) lymphoma cells, but not T14 (Vβ14+) and T5 (Vβ5+) neoplastic cells, strongly proliferated in vitro in the presence of SEB which interacts with the Vβ8 family of mouse TCRs. No alterations in the proliferative level of the Vβ8+ lymphoma cells were detected in the presence of SEI which was recently shown to interact with the Vβ5 chain in mice [8]. T5 cells increase their proliferative level in the presence of SEI. T14 cells showed a significant increase in their proliferative levels when co-cultured with splenocytes expressing the Sag encoded by MMTV BALB14 [17] whereas no alterations were detected when these cells were co-cultured with splenocytes infected with MMTV BALB2 which encodes for a Sag specific for Vβ2+ T cells [17]. Figure 2A-B depicts representative results.


Superantigens increase the survival of mice bearing T cell lymphomas by inducing apoptosis of neoplastic cells.

Mundiñano J, Berguer PM, Cabrera G, Lorenzo D, Nepomnaschy I, Piazzon I - PLoS ONE (2010)

Sags induce increases in the proliferative levels of cognate lymphoma T cells.(A–B) Proliferative response of lymphoma T cells in vitro. (A) Different numbers of T14 lymphoma cells were co-cultured with 0.7×105 mitomycin C-pretreated splenocytes from (•) non-infected AKR/J mice, (▪) MMTV BALB2-infected AKR/J mice or (▴) MMTV BALB14-infected AKR/J mice. The proliferative response was assessed by 3H-thymidine incorporation during the last 18 hr of a 1-day culture period. Data are expressed as the mean ± SD, n = 5, **p<0.01. (B) Different numbers of T8.2 lymphoma cells were co-cultured with 0.7×105 mitomycin C-pretreated intraperitoneal macrophages in the presence of 10 µg/ml of (▪) SEI, (▴) SEB or (•) PBS. The proliferative response was assessed by 3H-thymidine incorporation during the last 18 hr of a 1-day culture period. Data are expressed as the mean ± SD, n = 5, **p<0.01. (C) Proliferative response of lymphoma T cells in vivo. CFSE-stained T5 lymphoma cells (5×106) were transferred intraperitoneally into syngeneic AKR/J mice. The mice were divided into three groups (n = 3 per group) and received an intraperitoneal injection of 25 µg of SEB, SEI or PBS. Twenty four hours later cells were collected by intraperitoneal washing and CFSE fluorescence was analyzed. Overlayed histograms depict a representative example. All the experiments were performed three times with similar results.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3008744&req=5

pone-0015694-g002: Sags induce increases in the proliferative levels of cognate lymphoma T cells.(A–B) Proliferative response of lymphoma T cells in vitro. (A) Different numbers of T14 lymphoma cells were co-cultured with 0.7×105 mitomycin C-pretreated splenocytes from (•) non-infected AKR/J mice, (▪) MMTV BALB2-infected AKR/J mice or (▴) MMTV BALB14-infected AKR/J mice. The proliferative response was assessed by 3H-thymidine incorporation during the last 18 hr of a 1-day culture period. Data are expressed as the mean ± SD, n = 5, **p<0.01. (B) Different numbers of T8.2 lymphoma cells were co-cultured with 0.7×105 mitomycin C-pretreated intraperitoneal macrophages in the presence of 10 µg/ml of (▪) SEI, (▴) SEB or (•) PBS. The proliferative response was assessed by 3H-thymidine incorporation during the last 18 hr of a 1-day culture period. Data are expressed as the mean ± SD, n = 5, **p<0.01. (C) Proliferative response of lymphoma T cells in vivo. CFSE-stained T5 lymphoma cells (5×106) were transferred intraperitoneally into syngeneic AKR/J mice. The mice were divided into three groups (n = 3 per group) and received an intraperitoneal injection of 25 µg of SEB, SEI or PBS. Twenty four hours later cells were collected by intraperitoneal washing and CFSE fluorescence was analyzed. Overlayed histograms depict a representative example. All the experiments were performed three times with similar results.
Mentions: The ability of bacterial and viral Sags to increase the in vitro proliferation of cognate lymphoma T cells was first investigated. T8 and T8.2 (Vβ8.1,8.2+) lymphoma cells, but not T14 (Vβ14+) and T5 (Vβ5+) neoplastic cells, strongly proliferated in vitro in the presence of SEB which interacts with the Vβ8 family of mouse TCRs. No alterations in the proliferative level of the Vβ8+ lymphoma cells were detected in the presence of SEI which was recently shown to interact with the Vβ5 chain in mice [8]. T5 cells increase their proliferative level in the presence of SEI. T14 cells showed a significant increase in their proliferative levels when co-cultured with splenocytes expressing the Sag encoded by MMTV BALB14 [17] whereas no alterations were detected when these cells were co-cultured with splenocytes infected with MMTV BALB2 which encodes for a Sag specific for Vβ2+ T cells [17]. Figure 2A-B depicts representative results.

Bottom Line: Superantigens bind to major histocompatibility complex class II molecules and interact with T cells expressing a particular T cell receptor Vβ inducing a strong proliferation/deletion response of the superantigen-reactive T cells.However, there have been no attempts to investigate the ability of Sags to induce apoptosis in neoplastic T cells by signaling through the Vβ region of their TCR.The possibility of a therapeutic use of superantigens in lymphoma/leukemia T cell malignancies is discussed.

View Article: PubMed Central - PubMed

Affiliation: ILEX-CONICET, División Medicina Experimental, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.

ABSTRACT
Superantigens bind to major histocompatibility complex class II molecules and interact with T cells expressing a particular T cell receptor Vβ inducing a strong proliferation/deletion response of the superantigen-reactive T cells. However, there have been no attempts to investigate the ability of Sags to induce apoptosis in neoplastic T cells by signaling through the Vβ region of their TCR. In the present study we show that bacterial and MMTV-encoded superantigens induce the apoptosis of AKR/J cognate lymphoma T cells both in vitro and in vivo. The Fas-Fas-L pathway was shown to be involved in the apoptosis of lymphoma T cells induced by bacterial superantigens. In vivo exposure to bacterial superantigens was able to improve the survival of lymphoma bearing mice. Moreover, the permanent expression of a retroviral encoded superantigen induced the complete remission of an aggressive lymphoma in a high percentage of mice. The possibility of a therapeutic use of superantigens in lymphoma/leukemia T cell malignancies is discussed.

Show MeSH
Related in: MedlinePlus