Jeremy O’Sullivan | Northwestern University (original) (raw)

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Papers by Jeremy O’Sullivan

Research paper thumbnail of CD8+ T cells adversely effect their own memory potential via the regulation of the IL-12/IL-15R{alpha} axis

The Journal of Immunology, Apr 1, 2011

Research paper thumbnail of Engagement of NK receptor NKG2D, but not 2B4, results in self-reactive CD8+T cells and autoimmune vitiligo

Autoimmunity, 2011

In this study, we demonstrate that engagement of two different natural killer receptors (NKRs) ca... more In this study, we demonstrate that engagement of two different natural killer receptors (NKRs) can lead to contrasting effects in the development of self-reactive CD8+T cells and autoimmune vitiligo. Specifically, using a mouse model, we show that CD8+T-cell targeting of a melanocyte antigen, tyrosinase-related protein-1 (TRP-1) in combination with delivery of the NKG2D ligands (Rae-1ϵ or H60), results in strong CD8+T-cell responses against TRP-1 and in the development of autoimmune vitiligo. In contrast, targeting of TRP-1 in combination with delivery of CD48, the natural ligand for the NKR 2B4, leads to reduced formation of TRP-1-reactive CD8+T-cell responses and decreased development of vitiligo. These data indicate that autoimmune vitiligo is limited by insufficient signals, despite plentiful self-reactive T cells in the peripheral immune system. To our knowledge, this is the first experimental evidence supporting the role of NKRs in modulating CD8+T-cell autoimmune vitiligo. This study supports the utilization of NKR signaling as a therapeutic avenue toward prevention of vitiligo and other autoimmune diseases.

Research paper thumbnail of NKG2D signaling on CD8+ T cells represses T-bet and rescues CD4-unhelped CD8+ T cell memory recall but not effector responses

Nature Medicine, 2012

CD4-unhelped CD8 + T cells are functionally-defective cells primed in the absence of CD4 + T cell... more CD4-unhelped CD8 + T cells are functionally-defective cells primed in the absence of CD4 + T cell help and present a critical problem. Based on the co-stimulatory and non-canonical roles of NKG2D on CD8 + T cells, we investigated its ability to rescue these immunologically-impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, responses. NKG2D-mediated rescue is

Research paper thumbnail of Development of Tumor-Infiltrating CD8+ T Cell Memory Precursor Effector Cells and Antimelanoma Memory Responses Are the Result of Vaccination and TGF-  Blockade during the Perioperative Period of Tumor Resection

The Journal of Immunology, 2011

Research paper thumbnail of CD8 Co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression

Cancer Immunology, Immunotherapy, 2011

CD8 ? T cell function depends on a finely orchestrated balance of activation/suppression signals.... more CD8 ? T cell function depends on a finely orchestrated balance of activation/suppression signals. While the stimulatory role of the CD8 co-receptor and pleiotropic capabilities of TGF-b have been studied individually, the influence of CD8 co-receptor on TGF-b function in CD8 ? T cells is unknown. Here, we show that while CD8 enhances T cell activation, it also enhances susceptibility to TGF-b-mediated immune suppression. Using Jurkat cells expressing a full-length, truncated or no abCD8 molecule, we demonstrate that cells expressing fulllength abCD8 were highly susceptible, abCD8-truncated cells were partially susceptible, and CD8-deficient cells were completely resistant to suppression by TGF-b. Additionally, we determined that inhibition of Lck rendered mouse CD8 ? T cells highly resistant to TGF-b suppression. Resistance was not associated with TGF-b receptor expression but did correlate with decreased Smad3 and increased Smad7 levels. These findings highlight a previously unrecognized third role for CD8 co-receptor which appears to prepare activated CD8 ? T cells for response to TGF-b. Based on the important role which TGF-b-mediated suppression plays in tumor immunology, these findings unveil necessary considerations in formulation of CD8 ? T cell-related cancer immunotherapy strategies.

Research paper thumbnail of Priming with very low-affinity peptide ligands gives rise to CD8+ T-cell effectors with enhanced function but with greater susceptibility to transforming growth factor (TGF)β-mediated suppression

Cancer Immunology, Immunotherapy, 2011

While the effects of TCR affinity and TGFβ on CD8 + T-cell function have been studied individuall... more While the effects of TCR affinity and TGFβ on CD8 + T-cell function have been studied individually, the manner in which TCR affinity dictates susceptibility to TGFβ-mediated suppression remains unknown. To address this issue, we utilized OVA altered peptide ligands (APLs) of different affinities in the OT-I model. We demonstrate that while decreased TCR ligand affinity initially results in weakened responses, such interactions prime the resultant effector cells to respond more strongly to cognate antigen upon secondary exposure. Despite this, responses by CD8 + T cells primed with lower-affinity TCR ligands are more effectively regulated by TGFβ. Susceptibility to TGFβ-mediated suppression is associated with downregulation of RGS3, a recently recognized negative regulator of TGFβ signaling, but not expression of TGFβ receptors I/ © Springer-Verlag 2011 jguevara@uchicago.edu . Electronic supplementary material The online version of this article (II. These results suggest a novel tolerance mechanism whereby CD8 + T cells are discriminately regulated by TGFβ according to the affinity of the ligand on which they were initially primed. In addition, because of the major role played by TGFβ in tumor-induced immune suppression, these results identify the affinity of the priming ligand as a primary concern in CD8 + T-cell-mediated cancer immunotherapeutic strategies.

Research paper thumbnail of Rescuing "helpless" CD8+ T cell Memory Responses by Activating NK Receptor NKG2D during Priming

The Faseb Journal, Apr 1, 2008

Research paper thumbnail of CD8+ T Cells Sabotage Their Own Memory Potential through IFN- -Dependent Modification of the IL-12/IL-15 Receptor   Axis on Dendritic Cells

The Journal of Immunology, 2012

CD8 + T cell responses have been shown to be regulated by dendritic cells (DCs) and CD4 + T cells... more CD8 + T cell responses have been shown to be regulated by dendritic cells (DCs) and CD4 + T cells, leading to the tenet that CD8 + T cells play a passive role in their own differentiation. In contrast, by using a DNA vaccination model, to separate the events of vaccination from those of CD8 + T cell priming, we demonstrate that CD8 + T cells, themselves, actively limit their own memory potential through CD8 + T cell-derived IFN-g-dependent modification of the IL-12/IL-15Ra axis on DCs. Such CD8 + T cell-driven cytokine alterations result in increased T-bet and decreased Bcl-2 expression, and thus decreased memory progenitor formation. These results identify an unrecognized role for CD8 + T cells in the regulation of their own effector differentiation fate and a previously uncharacterized relationship between the balance of inflammation and memory formation.

Research paper thumbnail of CD8 Co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression

Cancer Immunology, Immunotherapy, 2011

CD8 ? T cell function depends on a finely orchestrated balance of activation/suppression signals.... more CD8 ? T cell function depends on a finely orchestrated balance of activation/suppression signals. While the stimulatory role of the CD8 co-receptor and pleiotropic capabilities of TGF-b have been studied individually, the influence of CD8 co-receptor on TGF-b function in CD8 ? T cells is unknown. Here, we show that while CD8 enhances T cell activation, it also enhances susceptibility to TGF-b-mediated immune suppression. Using Jurkat cells expressing a full-length, truncated or no abCD8 molecule, we demonstrate that cells expressing fulllength abCD8 were highly susceptible, abCD8-truncated cells were partially susceptible, and CD8-deficient cells were completely resistant to suppression by TGF-b. Additionally, we determined that inhibition of Lck rendered mouse CD8 ? T cells highly resistant to TGF-b suppression. Resistance was not associated with TGF-b receptor expression but did correlate with decreased Smad3 and increased Smad7 levels. These findings highlight a previously unrecognized third role for CD8 co-receptor which appears to prepare activated CD8 ? T cells for response to TGF-b. Based on the important role which TGF-b-mediated suppression plays in tumor immunology, these findings unveil necessary considerations in formulation of CD8 ? T cell-related cancer immunotherapy strategies.

Research paper thumbnail of Priming with very low affinity peptide ligands gives rise to CD8+ T cell effectors with enhanced function but with greater susceptibility to TGF{beta}-mediated suppression

The Journal of Immunology, Apr 1, 2011

While the effects of TCR affinity and TGFb on CD8 ? T-cell function have been studied individuall... more While the effects of TCR affinity and TGFb on CD8 ? T-cell function have been studied individually, the manner in which TCR affinity dictates susceptibility to TGFb-mediated suppression remains unknown. To address this issue, we utilized OVA altered peptide ligands (APLs) of different affinities in the OT-I model. We demonstrate that while decreased TCR ligand affinity initially results in weakened responses, such interactions prime the resultant effector cells to respond more strongly to cognate antigen upon secondary exposure. Despite this, responses by CD8 ? T cells primed with lower-affinity TCR ligands are more effectively regulated by TGFb. Susceptibility to TGFbmediated suppression is associated with downregulation of RGS3, a recently recognized negative regulator of TGFb signaling, but not expression of TGFb receptors I/II. These results suggest a novel tolerance mechanism whereby CD8 ? T cells are discriminately regulated by TGFb according to the affinity of the ligand on which they were initially primed. In addition, because of the major role played by TGFb in tumor-induced immune suppression, these results identify the affinity of the priming ligand as a primary concern in CD8 ? T-cell-mediated cancer immunotherapeutic strategies.

Research paper thumbnail of CD8+ T cells adversely effect their own memory potential via the regulation of the IL-12/IL-15R{alpha} axis

The Journal of Immunology, Apr 1, 2011

Research paper thumbnail of Engagement of NK receptor NKG2D, but not 2B4, results in self-reactive CD8+T cells and autoimmune vitiligo

Autoimmunity, 2011

In this study, we demonstrate that engagement of two different natural killer receptors (NKRs) ca... more In this study, we demonstrate that engagement of two different natural killer receptors (NKRs) can lead to contrasting effects in the development of self-reactive CD8+T cells and autoimmune vitiligo. Specifically, using a mouse model, we show that CD8+T-cell targeting of a melanocyte antigen, tyrosinase-related protein-1 (TRP-1) in combination with delivery of the NKG2D ligands (Rae-1ϵ or H60), results in strong CD8+T-cell responses against TRP-1 and in the development of autoimmune vitiligo. In contrast, targeting of TRP-1 in combination with delivery of CD48, the natural ligand for the NKR 2B4, leads to reduced formation of TRP-1-reactive CD8+T-cell responses and decreased development of vitiligo. These data indicate that autoimmune vitiligo is limited by insufficient signals, despite plentiful self-reactive T cells in the peripheral immune system. To our knowledge, this is the first experimental evidence supporting the role of NKRs in modulating CD8+T-cell autoimmune vitiligo. This study supports the utilization of NKR signaling as a therapeutic avenue toward prevention of vitiligo and other autoimmune diseases.

Research paper thumbnail of NKG2D signaling on CD8+ T cells represses T-bet and rescues CD4-unhelped CD8+ T cell memory recall but not effector responses

Nature Medicine, 2012

CD4-unhelped CD8 + T cells are functionally-defective cells primed in the absence of CD4 + T cell... more CD4-unhelped CD8 + T cells are functionally-defective cells primed in the absence of CD4 + T cell help and present a critical problem. Based on the co-stimulatory and non-canonical roles of NKG2D on CD8 + T cells, we investigated its ability to rescue these immunologically-impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, responses. NKG2D-mediated rescue is

Research paper thumbnail of Development of Tumor-Infiltrating CD8+ T Cell Memory Precursor Effector Cells and Antimelanoma Memory Responses Are the Result of Vaccination and TGF-  Blockade during the Perioperative Period of Tumor Resection

The Journal of Immunology, 2011

Research paper thumbnail of CD8 Co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression

Cancer Immunology, Immunotherapy, 2011

CD8 ? T cell function depends on a finely orchestrated balance of activation/suppression signals.... more CD8 ? T cell function depends on a finely orchestrated balance of activation/suppression signals. While the stimulatory role of the CD8 co-receptor and pleiotropic capabilities of TGF-b have been studied individually, the influence of CD8 co-receptor on TGF-b function in CD8 ? T cells is unknown. Here, we show that while CD8 enhances T cell activation, it also enhances susceptibility to TGF-b-mediated immune suppression. Using Jurkat cells expressing a full-length, truncated or no abCD8 molecule, we demonstrate that cells expressing fulllength abCD8 were highly susceptible, abCD8-truncated cells were partially susceptible, and CD8-deficient cells were completely resistant to suppression by TGF-b. Additionally, we determined that inhibition of Lck rendered mouse CD8 ? T cells highly resistant to TGF-b suppression. Resistance was not associated with TGF-b receptor expression but did correlate with decreased Smad3 and increased Smad7 levels. These findings highlight a previously unrecognized third role for CD8 co-receptor which appears to prepare activated CD8 ? T cells for response to TGF-b. Based on the important role which TGF-b-mediated suppression plays in tumor immunology, these findings unveil necessary considerations in formulation of CD8 ? T cell-related cancer immunotherapy strategies.

Research paper thumbnail of Priming with very low-affinity peptide ligands gives rise to CD8+ T-cell effectors with enhanced function but with greater susceptibility to transforming growth factor (TGF)β-mediated suppression

Cancer Immunology, Immunotherapy, 2011

While the effects of TCR affinity and TGFβ on CD8 + T-cell function have been studied individuall... more While the effects of TCR affinity and TGFβ on CD8 + T-cell function have been studied individually, the manner in which TCR affinity dictates susceptibility to TGFβ-mediated suppression remains unknown. To address this issue, we utilized OVA altered peptide ligands (APLs) of different affinities in the OT-I model. We demonstrate that while decreased TCR ligand affinity initially results in weakened responses, such interactions prime the resultant effector cells to respond more strongly to cognate antigen upon secondary exposure. Despite this, responses by CD8 + T cells primed with lower-affinity TCR ligands are more effectively regulated by TGFβ. Susceptibility to TGFβ-mediated suppression is associated with downregulation of RGS3, a recently recognized negative regulator of TGFβ signaling, but not expression of TGFβ receptors I/ © Springer-Verlag 2011 jguevara@uchicago.edu . Electronic supplementary material The online version of this article (II. These results suggest a novel tolerance mechanism whereby CD8 + T cells are discriminately regulated by TGFβ according to the affinity of the ligand on which they were initially primed. In addition, because of the major role played by TGFβ in tumor-induced immune suppression, these results identify the affinity of the priming ligand as a primary concern in CD8 + T-cell-mediated cancer immunotherapeutic strategies.

Research paper thumbnail of Rescuing "helpless" CD8+ T cell Memory Responses by Activating NK Receptor NKG2D during Priming

The Faseb Journal, Apr 1, 2008

Research paper thumbnail of CD8+ T Cells Sabotage Their Own Memory Potential through IFN- -Dependent Modification of the IL-12/IL-15 Receptor   Axis on Dendritic Cells

The Journal of Immunology, 2012

CD8 + T cell responses have been shown to be regulated by dendritic cells (DCs) and CD4 + T cells... more CD8 + T cell responses have been shown to be regulated by dendritic cells (DCs) and CD4 + T cells, leading to the tenet that CD8 + T cells play a passive role in their own differentiation. In contrast, by using a DNA vaccination model, to separate the events of vaccination from those of CD8 + T cell priming, we demonstrate that CD8 + T cells, themselves, actively limit their own memory potential through CD8 + T cell-derived IFN-g-dependent modification of the IL-12/IL-15Ra axis on DCs. Such CD8 + T cell-driven cytokine alterations result in increased T-bet and decreased Bcl-2 expression, and thus decreased memory progenitor formation. These results identify an unrecognized role for CD8 + T cells in the regulation of their own effector differentiation fate and a previously uncharacterized relationship between the balance of inflammation and memory formation.

Research paper thumbnail of CD8 Co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression

Cancer Immunology, Immunotherapy, 2011

CD8 ? T cell function depends on a finely orchestrated balance of activation/suppression signals.... more CD8 ? T cell function depends on a finely orchestrated balance of activation/suppression signals. While the stimulatory role of the CD8 co-receptor and pleiotropic capabilities of TGF-b have been studied individually, the influence of CD8 co-receptor on TGF-b function in CD8 ? T cells is unknown. Here, we show that while CD8 enhances T cell activation, it also enhances susceptibility to TGF-b-mediated immune suppression. Using Jurkat cells expressing a full-length, truncated or no abCD8 molecule, we demonstrate that cells expressing fulllength abCD8 were highly susceptible, abCD8-truncated cells were partially susceptible, and CD8-deficient cells were completely resistant to suppression by TGF-b. Additionally, we determined that inhibition of Lck rendered mouse CD8 ? T cells highly resistant to TGF-b suppression. Resistance was not associated with TGF-b receptor expression but did correlate with decreased Smad3 and increased Smad7 levels. These findings highlight a previously unrecognized third role for CD8 co-receptor which appears to prepare activated CD8 ? T cells for response to TGF-b. Based on the important role which TGF-b-mediated suppression plays in tumor immunology, these findings unveil necessary considerations in formulation of CD8 ? T cell-related cancer immunotherapy strategies.

Research paper thumbnail of Priming with very low affinity peptide ligands gives rise to CD8+ T cell effectors with enhanced function but with greater susceptibility to TGF{beta}-mediated suppression

The Journal of Immunology, Apr 1, 2011

While the effects of TCR affinity and TGFb on CD8 ? T-cell function have been studied individuall... more While the effects of TCR affinity and TGFb on CD8 ? T-cell function have been studied individually, the manner in which TCR affinity dictates susceptibility to TGFb-mediated suppression remains unknown. To address this issue, we utilized OVA altered peptide ligands (APLs) of different affinities in the OT-I model. We demonstrate that while decreased TCR ligand affinity initially results in weakened responses, such interactions prime the resultant effector cells to respond more strongly to cognate antigen upon secondary exposure. Despite this, responses by CD8 ? T cells primed with lower-affinity TCR ligands are more effectively regulated by TGFb. Susceptibility to TGFbmediated suppression is associated with downregulation of RGS3, a recently recognized negative regulator of TGFb signaling, but not expression of TGFb receptors I/II. These results suggest a novel tolerance mechanism whereby CD8 ? T cells are discriminately regulated by TGFb according to the affinity of the ligand on which they were initially primed. In addition, because of the major role played by TGFb in tumor-induced immune suppression, these results identify the affinity of the priming ligand as a primary concern in CD8 ? T-cell-mediated cancer immunotherapeutic strategies.