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Abacavir-reactive memory T cells are present in drug naïve individuals.

Lucas A, Lucas M, Strhyn A, Keane NM, McKinnon E, Pavlos R, Moran EM, Meyer-Pannwitt V, Gaudieri S, D'Orsogna L, Kalams S, Ostrov DA, Buus S, Peters B, Mallal S, Phillips E - PLoS ONE (2015)

Bottom Line: Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug.Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors.Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia.

ABSTRACT

Background: Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.

Methods: To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.

Results: Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.

Conclusions: We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.

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Immunization of an HLA-B*57:01 donor with the yellow fever vaccine results in the expansion of populations of CD8+ T cells that detect both the wild type epitope and abacavir dependent variant epitopes.T cells expanded from a yellow fever vaccinated B*57:01 donor were labelled with anti-CD3 and CD8 and a mixture of K9F-B*57:01-PE, K9A-ABC-B*57:01-APC, and K9V-ABC-B*57:01-BV421 tetramers. CD8+ T cells were gated and the combination of K9F-B*57:01-PE and K9A-ABC-B*57:01-APC tetramer stained CD8+ T cells are shown in A. Subpopulations of tetramer stained cells are gated: P4 (pink); P5 (yellow); P6 (green); P7 (blue); P8 (orange); P9 (purple). The combinations of K9F-B*57:01-PE and K9V-ABC-B*57:01-BV421 tetramer stained CD8+ T cells are shown in B. The colors identify the position of the gated tetramer stained populations in panel A.
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pone.0117160.g006: Immunization of an HLA-B*57:01 donor with the yellow fever vaccine results in the expansion of populations of CD8+ T cells that detect both the wild type epitope and abacavir dependent variant epitopes.T cells expanded from a yellow fever vaccinated B*57:01 donor were labelled with anti-CD3 and CD8 and a mixture of K9F-B*57:01-PE, K9A-ABC-B*57:01-APC, and K9V-ABC-B*57:01-BV421 tetramers. CD8+ T cells were gated and the combination of K9F-B*57:01-PE and K9A-ABC-B*57:01-APC tetramer stained CD8+ T cells are shown in A. Subpopulations of tetramer stained cells are gated: P4 (pink); P5 (yellow); P6 (green); P7 (blue); P8 (orange); P9 (purple). The combinations of K9F-B*57:01-PE and K9V-ABC-B*57:01-BV421 tetramer stained CD8+ T cells are shown in B. The colors identify the position of the gated tetramer stained populations in panel A.

Mentions: In both donors, one of which is shown in Fig. 6, the K9F-B*57:01 CD8+ T-cell response was polyclonal and could be separated into at least six populations based on T-cell cross-recognition of the abacavir bound variants, K9A-ABC-B*57:01 and K9V-ABC-B*57:01. The first population (gate P4; Fig. 6) recognized only the K9F epitope and none of the variants. The second and third populations (gate P7 and P8; Fig. 6) recognized the K9F epitope with a high staining intensity and cross-recognized the K9A-ABC-B*57:01 variant with an intermediate staining intensity, but not the K9V-ABC-B*57:01 variant. The fourth population (gate P9; Fig. 6) recognized the K9F epitope with an intermediate staining intensity and cross-recognized both the K9A-ABC-B*57:01 and the K9V-ABC-B*57:01 variant with intermediate staining intensities. The fifth population (gate P6; Fig. 6) recognized the K9F epitope with an intermediate staining intensity and cross-recognized both the K9A-ABC-B*57:01 and the K9V-ABC-B*57:01 variant with high staining intensities. The sixth population (gate P5; Fig. 6) recognized the K9F epitope with a low staining intensity and cross-recognized both the K9A-ABC-B*57:01 and the K9V-ABC-B*57:01 variant with intermediate staining intensities.


Abacavir-reactive memory T cells are present in drug naïve individuals.

Lucas A, Lucas M, Strhyn A, Keane NM, McKinnon E, Pavlos R, Moran EM, Meyer-Pannwitt V, Gaudieri S, D'Orsogna L, Kalams S, Ostrov DA, Buus S, Peters B, Mallal S, Phillips E - PLoS ONE (2015)

Immunization of an HLA-B*57:01 donor with the yellow fever vaccine results in the expansion of populations of CD8+ T cells that detect both the wild type epitope and abacavir dependent variant epitopes.T cells expanded from a yellow fever vaccinated B*57:01 donor were labelled with anti-CD3 and CD8 and a mixture of K9F-B*57:01-PE, K9A-ABC-B*57:01-APC, and K9V-ABC-B*57:01-BV421 tetramers. CD8+ T cells were gated and the combination of K9F-B*57:01-PE and K9A-ABC-B*57:01-APC tetramer stained CD8+ T cells are shown in A. Subpopulations of tetramer stained cells are gated: P4 (pink); P5 (yellow); P6 (green); P7 (blue); P8 (orange); P9 (purple). The combinations of K9F-B*57:01-PE and K9V-ABC-B*57:01-BV421 tetramer stained CD8+ T cells are shown in B. The colors identify the position of the gated tetramer stained populations in panel A.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4326126&req=5

pone.0117160.g006: Immunization of an HLA-B*57:01 donor with the yellow fever vaccine results in the expansion of populations of CD8+ T cells that detect both the wild type epitope and abacavir dependent variant epitopes.T cells expanded from a yellow fever vaccinated B*57:01 donor were labelled with anti-CD3 and CD8 and a mixture of K9F-B*57:01-PE, K9A-ABC-B*57:01-APC, and K9V-ABC-B*57:01-BV421 tetramers. CD8+ T cells were gated and the combination of K9F-B*57:01-PE and K9A-ABC-B*57:01-APC tetramer stained CD8+ T cells are shown in A. Subpopulations of tetramer stained cells are gated: P4 (pink); P5 (yellow); P6 (green); P7 (blue); P8 (orange); P9 (purple). The combinations of K9F-B*57:01-PE and K9V-ABC-B*57:01-BV421 tetramer stained CD8+ T cells are shown in B. The colors identify the position of the gated tetramer stained populations in panel A.
Mentions: In both donors, one of which is shown in Fig. 6, the K9F-B*57:01 CD8+ T-cell response was polyclonal and could be separated into at least six populations based on T-cell cross-recognition of the abacavir bound variants, K9A-ABC-B*57:01 and K9V-ABC-B*57:01. The first population (gate P4; Fig. 6) recognized only the K9F epitope and none of the variants. The second and third populations (gate P7 and P8; Fig. 6) recognized the K9F epitope with a high staining intensity and cross-recognized the K9A-ABC-B*57:01 variant with an intermediate staining intensity, but not the K9V-ABC-B*57:01 variant. The fourth population (gate P9; Fig. 6) recognized the K9F epitope with an intermediate staining intensity and cross-recognized both the K9A-ABC-B*57:01 and the K9V-ABC-B*57:01 variant with intermediate staining intensities. The fifth population (gate P6; Fig. 6) recognized the K9F epitope with an intermediate staining intensity and cross-recognized both the K9A-ABC-B*57:01 and the K9V-ABC-B*57:01 variant with high staining intensities. The sixth population (gate P5; Fig. 6) recognized the K9F epitope with a low staining intensity and cross-recognized both the K9A-ABC-B*57:01 and the K9V-ABC-B*57:01 variant with intermediate staining intensities.

Bottom Line: Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug.Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors.Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia.

ABSTRACT

Background: Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.

Methods: To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.

Results: Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.

Conclusions: We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.

Show MeSH
Related in: MedlinePlus