John K. Northrop, MD, PhD (original) (raw)
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Papers by John K. Northrop, MD, PhD
Online Journal of Health Ethics, 2019
Generating long-lasting, protective cellular immunity via vaccination is critical for combating m... more Generating long-lasting, protective cellular immunity via vaccination is critical for combating major and emerging infectious diseases. Data presented here provide new insights into the molecular mechanisms important for the enhanced immune protection afforded by memory CD8 T cells. CD4 T cell help is critical for the differentiation of CD8 T cells into long-lasting, functional memory. The generation of central memory CD8 T cells, which are stably maintained and robustly proliferate to control reinfection, is impaired without CD4 T cell help. Memory CD8 T cells generated without CD4 T cell help are also deficient in epigenetic remodeling at the lfng and ll2 loci and are incapable of immediate, high-level cytokine production. Inhibition of histone deacetylase activity in unhelped memory CD8 T cells increases total cellular histone acetylation, including at the lfng enhancer and promoter. Most significantly, enhancing histone acetylation in unhelped CD8 T cells during priming restores immediate cytokine production, survival and immune protection against infection by the resultant memory CD8 T cells. This indicates that histone acetylation is a general molecular mechanism for enhanced functionality in memory CD8 T cells. CD4 T cells are absolutely required for increased histone acetylation and the delivery of T help to CD8 T cells might be mediated in part by IL-21. These findings have important implications for developing vaccine strategies that induce high quality CD8 T cell memory, not just high quantity
Journal of the American Academy of Psychiatry and the Law Online, Jun 1, 2013
Psychiatric Expert Testimony: Emerging Applications, 2015
The Journal of Immunology, 2008
Memory CD8 T cells, unlike their naive precursors, are capable of rapidly producing high levels o... more Memory CD8 T cells, unlike their naive precursors, are capable of rapidly producing high levels of cytokines, killing target cells, and proliferating into numerous secondary effectors immediately upon Ag encounter. This ready-to-respond state contributes to their superior ability to confer protective immunity, yet the underlying molecular basis remains unknown. In this study, we show that memory CD8 T cells have increased histone acetylation compared with naive CD8 T cells; however, those activated without CD4 T cell help (“unhelped”) remain hypoacetylated and fail to develop into functional, protective memory. Treatment with a histone deacetylase inhibitor during activation results in increased histone acetylation in unhelped CD8 T cells and restores their ability to differentiate into functional memory cells capable of immediate cytokine production and providing protective immunity. These results demonstrate that CD4 T help-dependent chromatin remodeling provides a molecular basis...
The Journal of Immunology, 2006
Memory T cells (TM) are able to rapidly exert effector functions, including immediate effector cy... more Memory T cells (TM) are able to rapidly exert effector functions, including immediate effector cytokine production upon re-encounter with Ag, which is critical for protective immunity. Furthermore, this poised state is maintained as TM undergo homeostatic proliferation over time. We examined the molecular basis underlying this enhanced functional capacity in CD8 TM by comparing them to defective CD8 TM generated in the absence of CD4 T cells. Unhelped CD8 TM are defective in many functions, including the immediate expression of cytokines, such as IL-2 and IFN-γ. Our data show that this defect in IL-2 and IFN-γ production is independent of clonal selection, functional avidity maturation, and the integrity of proximal TCR signaling, but rather involves epigenetic modification of these cytokine genes. Activated Ag-specific CD8 T cells exhibit rapid DNA demethylation at the IL-2 and IFN-γ loci and substantial histone acetylation at the IFN-γ promoter and enhancer regions. These epigenet...
The Journal of Experimental Medicine, 2007
Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of ... more Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8+ T cells and self-renewal of central–memory CD8+ T cells. We now show that T-bet represses transcription of IL-7Rα and drives differentiation of effector and effector–memory CD8+ T cells at the expense of central–memory cells. We also found T-bet to be overexpressed in CD8+ T cells that differentiated in the absence of CD4+ T cell help, a condition that is associated with defective central–memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of “unhelped” memory CD8+ T cells. T-bet, thus, appears to function as a molecular switch between central– and effector–memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8+ T cells.
Current Opinion in Immunology, 2004
Generating long-lasting, protective CD8(+) T-cell memory via vaccination is critical for combatin... more Generating long-lasting, protective CD8(+) T-cell memory via vaccination is critical for combating infectious diseases. Advances in the past year have provided many new insights into how memory CD8(+) T cells are generated. It is now recognized that CD8(+) T cells differentiate from 'effector memory' cells into 'central memory' cells, which are stably maintained and confer superior protective immunity. Furthermore, CD4(+) T-cell help plays an important role in guiding the differentiation of CD8(+) T cells into long-lasting, functional memory. These findings have important implications for developing vaccine strategies that induce high-quality CD8(+) T-cell memory, not just high quantity.
Online Journal of Health Ethics, 2019
Generating long-lasting, protective cellular immunity via vaccination is critical for combating m... more Generating long-lasting, protective cellular immunity via vaccination is critical for combating major and emerging infectious diseases. Data presented here provide new insights into the molecular mechanisms important for the enhanced immune protection afforded by memory CD8 T cells. CD4 T cell help is critical for the differentiation of CD8 T cells into long-lasting, functional memory. The generation of central memory CD8 T cells, which are stably maintained and robustly proliferate to control reinfection, is impaired without CD4 T cell help. Memory CD8 T cells generated without CD4 T cell help are also deficient in epigenetic remodeling at the lfng and ll2 loci and are incapable of immediate, high-level cytokine production. Inhibition of histone deacetylase activity in unhelped memory CD8 T cells increases total cellular histone acetylation, including at the lfng enhancer and promoter. Most significantly, enhancing histone acetylation in unhelped CD8 T cells during priming restores immediate cytokine production, survival and immune protection against infection by the resultant memory CD8 T cells. This indicates that histone acetylation is a general molecular mechanism for enhanced functionality in memory CD8 T cells. CD4 T cells are absolutely required for increased histone acetylation and the delivery of T help to CD8 T cells might be mediated in part by IL-21. These findings have important implications for developing vaccine strategies that induce high quality CD8 T cell memory, not just high quantity
Journal of the American Academy of Psychiatry and the Law Online, Jun 1, 2013
Psychiatric Expert Testimony: Emerging Applications, 2015
The Journal of Immunology, 2008
Memory CD8 T cells, unlike their naive precursors, are capable of rapidly producing high levels o... more Memory CD8 T cells, unlike their naive precursors, are capable of rapidly producing high levels of cytokines, killing target cells, and proliferating into numerous secondary effectors immediately upon Ag encounter. This ready-to-respond state contributes to their superior ability to confer protective immunity, yet the underlying molecular basis remains unknown. In this study, we show that memory CD8 T cells have increased histone acetylation compared with naive CD8 T cells; however, those activated without CD4 T cell help (“unhelped”) remain hypoacetylated and fail to develop into functional, protective memory. Treatment with a histone deacetylase inhibitor during activation results in increased histone acetylation in unhelped CD8 T cells and restores their ability to differentiate into functional memory cells capable of immediate cytokine production and providing protective immunity. These results demonstrate that CD4 T help-dependent chromatin remodeling provides a molecular basis...
The Journal of Immunology, 2006
Memory T cells (TM) are able to rapidly exert effector functions, including immediate effector cy... more Memory T cells (TM) are able to rapidly exert effector functions, including immediate effector cytokine production upon re-encounter with Ag, which is critical for protective immunity. Furthermore, this poised state is maintained as TM undergo homeostatic proliferation over time. We examined the molecular basis underlying this enhanced functional capacity in CD8 TM by comparing them to defective CD8 TM generated in the absence of CD4 T cells. Unhelped CD8 TM are defective in many functions, including the immediate expression of cytokines, such as IL-2 and IFN-γ. Our data show that this defect in IL-2 and IFN-γ production is independent of clonal selection, functional avidity maturation, and the integrity of proximal TCR signaling, but rather involves epigenetic modification of these cytokine genes. Activated Ag-specific CD8 T cells exhibit rapid DNA demethylation at the IL-2 and IFN-γ loci and substantial histone acetylation at the IFN-γ promoter and enhancer regions. These epigenet...
The Journal of Experimental Medicine, 2007
Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of ... more Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8+ T cells and self-renewal of central–memory CD8+ T cells. We now show that T-bet represses transcription of IL-7Rα and drives differentiation of effector and effector–memory CD8+ T cells at the expense of central–memory cells. We also found T-bet to be overexpressed in CD8+ T cells that differentiated in the absence of CD4+ T cell help, a condition that is associated with defective central–memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of “unhelped” memory CD8+ T cells. T-bet, thus, appears to function as a molecular switch between central– and effector–memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8+ T cells.
Current Opinion in Immunology, 2004
Generating long-lasting, protective CD8(+) T-cell memory via vaccination is critical for combatin... more Generating long-lasting, protective CD8(+) T-cell memory via vaccination is critical for combating infectious diseases. Advances in the past year have provided many new insights into how memory CD8(+) T cells are generated. It is now recognized that CD8(+) T cells differentiate from 'effector memory' cells into 'central memory' cells, which are stably maintained and confer superior protective immunity. Furthermore, CD4(+) T-cell help plays an important role in guiding the differentiation of CD8(+) T cells into long-lasting, functional memory. These findings have important implications for developing vaccine strategies that induce high-quality CD8(+) T-cell memory, not just high quantity.