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Jay Berzofsky

National Institutes of Health, Vaccine Branch, National Cancer Institute, Faculty Member

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Universitat de Barcelona

South Dakota State University

Ulrich Schmölcke

Leibniz-Zentrum für Archäologie

Auburn University

University of Trento

Viacheslav Kuleshov

Stockholm University

Haramaya university

Aleme Asres (PhD)

Wollo University

Università di trento

Jerome Courduries

Université Toulouse II Jean Jaurès

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Papers by Jay Berzofsky

The Murine Kupffer Cell

Journal of Immunology, Dec 1, 1979

Murine Kupffer cells, the tissue macrohages of the liver, were isolated by collagenase digestion,... more Murine Kupffer cells, the tissue macrohages of the liver, were isolated by collagenase digestion, differential sedimentation over Metrizamide, and glass adherence. The resultant cell population was more than 86% phagocytic, and 95% of cell stained positively for α-naphtyl butyratc esterase activity. The cells also had cell surface receptors for complement (C) and the Fc portion of IgG. In additon, a large proportion of Kupffer cells was shown to bear Ia antigens: about half of the cells bore I-A subregion-encoded antigens. Kupffer cell populations were capable of reconstituting antigen-stumulated proliferative responses of antigen-primed, macrophage-depleted, lymph node T cells. The ability to reconstitute proliferation was enriched in the adheren population and was resistant to radiation and treatment with an anti-Thy antiserum and C. We conclude that isolated murine Kupffer cells bear the Ia phenotype of accessory cells that function in antigen presentation and that Kupffer cells can paricipate in the induction of antigen-specific immune responses. These data suggest that Kupffer cells may play a role in modulating responses to enterically derived antigens.

This article cites 22 articles, 7 of which can be accessed free at:

Abstract LB-A06: Pipeline for High Throughput Analysis of Exosomes in Clinical Biofluids

Molecular Cancer Therapeutics, 2018

Purpose/Objective(s): Because Extracellular Vesicles (EVs) carry surface receptors that are chara... more Purpose/Objective(s): Because Extracellular Vesicles (EVs) carry surface receptors that are characteristic of their cells of origin, EVs have tremendous potential as non-invasive biomarkers for diagnosis, risk-stratification, treatment selection, and treatment monitoring. We developed a first-in-class pipeline to characterize EV heterogeneity and provide high-sensitivity quantification of informative EVs in biofluids before, during, and after treatment. By combining multiplex assays with high-resolution, single EV flow cytometric methods together into a Mutiplex-to-Single EV Analysis (Mt-SEA) pipeline, we are able to characterize a broad range of relevant EV subsets, while also accurately measuring the concentration of specific EV populations. Exploratory studies presented here validate the performance of Mt-SEA method by confirming strong correlations of liquid biopsy EV repertoires with tumor burden and responses to treatment. Furthermore, EV analysis with Mt-SEA may identify prev...

Effects of Cross-Presentation, Antigen Processing, and Peptide Binding in HIV Evasion of T Cell Immunity

Journal of immunology (Baltimore, Md. : 1950), 2018

Unlike cytosolic processing and presentation of viral Ags by virus-infected cells, Ags first expr... more Unlike cytosolic processing and presentation of viral Ags by virus-infected cells, Ags first expressed in infected nonprofessional APCs, such as CD4T cells in the case of HIV, are taken up by dendritic cells and cross-presented. This generally requires entry through the endocytic pathway, where endosomal proteases have first access for processing. Thus, understanding virus escape during cross-presentation requires an understanding of resistance to endosomal proteases, such as cathepsin S (CatS). We have modified HIV-1gp120 by mutating a key CatS cleavage site (ThrThr) in the V3 loop of the immunodominant epitope IGPGRAFYto IGPGRAFYto prevent digestion. We found this mutation to facilitate cross-presentation and provide evidence from MHC binding and X-ray crystallographic structural studies that this results from preservation of the epitope rather than an increased epitope affinity for the MHC class I molecule. In contrast, when the protein is expressed by a vaccinia virus in the cyt...

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Journal of immunology (Baltimore, Md. : 1950), May 1, 2017

T cells with high functional avidity can sense and respond to low levels of cognate Ag, a charact... more T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high-avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that v...

Recombinant vaccine viruses expressing IL-15 and methods using the same

Treatment of cancer via targeting of il-13 receptor-alpha2

Mucosal Cytotoxic T Lymphocyte Responses

Mucosal cytotoxic T lymphocyte responses

Overcoming CD4 deficiency to induce long-lived memory CD8+ CTL

Retrovirology, 2006

Human retroviruses and AIDS 1994

More detailed tables of contents are to be found within the various parts of the compendium. The ... more

Human retroviruses and AIDS, 1991. [CONTAINS GLOSSARY]

Thin repurIwevpcwmred eamvncarunlwfwvxh qanmurwdbymr~rwy Mlhc[JnlWd.S!mm Owerrrmcnt. Nciikrthc (J... more Thin repurIwevpcwmred eamvncarunlwfwvxh qanmurwdbymr~rwy Mlhc[JnlWd.S!mm Owerrrmcnt. Nciikrthc (Jnitd Slalm(h~rnmnl mcnnyngwrxy thcmvf, nvrcmryd Ihwlr cmployea, m-kc mIy wnrranly, csprcas ur lmpikvl, or uaurna qny la~l Iidklily tw rcepmci. hdily hw Ihe wtxmcy, uornplaeneu, IW udulneca of wry mhmvrmvm Wwrmlm tiwlt w prvwam didvnad, or rcprcmnl~thnl iis uu WIWAI w mfrin~wwntdy owned ri~hl~. Mar. crwe krcin m my vpmMiu wnmcrcml pdud, pwcna, of wrvww hy Irdc mne, lredenmrl, mmdedurer, IU dkrwmc dIEm m~naucaamrilyccmIIIuIc O; mrply IIS cndummcnl, wm. rrvand-lntn, or [morms hy he 1Mml .SYalcs( ivwcrnmcrvl or qny -gcnuy lhcrd. "Ilrc vicwn d wpmanrn d dwws cqwaced hcrwm do rmi nvttsmrily fimc Or rctld thi~wf Ihe [Jnild Shlen (bvcrnrrwnl wr any ~ncy lhcmL osAhrinlm LosAlar,IOSNational Laboratory lmsAlamos,New Mexico 87545 HUMAN RETROVIRUSES and AIDS 1991 A COMPILATION AND ANALYSIS OF NUCLEIC ACID

Comparative analysis of SIV-specific cellular immune responses induced by different vaccine platforms in rhesus macaques

Clinical Immunology, 2014

To identify the most promising vaccine candidates for combinatorial strategies, we compared five ... more

Humoral immunity induced by mucosal and/or systemic SIV-specific vaccine platforms suggests novel combinatorial approaches for enhancing responses

Clinical Immunology, 2014

Combinatorial HIV/SIV vaccine approaches targeting multiple arms of the immune system might impro... more Combinatorial HIV/SIV vaccine approaches targeting multiple arms of the immune system might improve protective efficacy. We compared SIV-specific humoral immunity induced in rhesus macaques by five vaccine regimens. Systemic regimens included ALVAC-SIVenv priming and Env boosting (ALVAC/Env); DNA immunization; and DNA plus Env co-immunization (DNA&Env). RepAd/Env combined mucosal replication-competent Ad-env priming with

TLR agonists and/or IL-15 adjuvanted mucosal SIV vaccine reduced gut CD4+ memory T cell loss in SIVmac251-challenged rhesus macaques

Vaccine, 2011

Adjuvant plays an important role in increasing and directing vaccine-induced immune responses. In... more Adjuvant plays an important role in increasing and directing vaccine-induced immune responses. In a previous study, we found that a mucosal SIV vaccine using a combination of IL-15 and TLR agonists as adjuvant mediated partial protection against SIVmac251 rectal challenge, whereas neither IL-15 nor TLR agonists alone as an adjuvant impacted the plasma viral loads. In this study, dissociation of CD4 + T cell preservation with viral loads was observed in the animals vaccinated with adjuvants. Significantly higher levels of memory CD4 + T cell numbers were preserved after SIVmac251 infection in the colons of the animals vaccinated with vaccine containing any of these adjuvants compared to no adjuvant. When we measured the viral-specific CD8 + tetramer responses in the colon lamina propria, we found significantly higher levels of gag, tat, and pol epitope tetramer + T cell responses in these animals compared to ones without adjuvant, even if some of the animals had similarly high viral loads. Furthermore, this CD4 + T preservation was positively correlated with increased levels of gag and Tat, but not pol tetramer + T cell responses, and inversely correlated with beta-chemokine expression. The pre-challenged APOBEC3G expression level, which has previously been shown inversely associated with viral loads, was further found positively correlated with CD4 + T cell number preservation. Overall, these data highlight one unrecognized role of adjuvant in HIV vaccine development, and show that vaccines can produce a surprising discordance between CD4 + T cell levels and SIV viral load.

Antibodies Directed Against the MHC-I Molecule H-2Dd Complexed with an Antigenic Peptide: Similarities to a T Cell Receptor with the Same Specificity

The Journal of Immunology, 2000

αβ TCRs, which use an Ab-like structure to form a combining site, recognize molecular complexes c... more αβ TCRs, which use an Ab-like structure to form a combining site, recognize molecular complexes consisting of peptides bound to MHC class I (MHC-I) or class II (MHC-II) molecules. To explore the similarities and differences between Ab and T cell recognition of similar structures, we have isolated two mAbs, KP14 and KP15, that specifically bind H-2Dd complexed with an HIV envelope gp160-derived peptide, P18-I10. These Abs are MHC and peptide specific. Fine specificity of mAb binding was analyzed using a panel of synthetic peptides, revealing similarities between the mAb and a cloned TCR with the same specificity. These two mAbs used the same VH and JH gene segments, but different D, Vκ, and Jκ genes. Administered in vivo, mAb KP15 blocked the induction of CTL specific for recombinant vaccinia virus-encoded gp160, indicating its ability to bind endogenously generated MHC/peptide complexes. Analysis of the fine specificity of these mAbs in the context of their encoded amino acid sequen...

Interplay of Cytokines and Adjuvants in the Regulation of Mucosal and Systemic HIV-Specific CTL

The Journal of Immunology, 2000

We examined the interplay between cytokines and adjuvants to optimize the induction of CTL by a m... more We examined the interplay between cytokines and adjuvants to optimize the induction of CTL by a mucosal HIV peptide vaccine. We show synergy between IL-12 and GM-CSF when administered together with the HIV peptide PCLUS3–18IIIB and cholera toxin (CT) in the induction of CTL activity and protection against mucosal viral transmission. Further, we examine the efficacy of mutant Escherichia coli labile toxin, LT(R192G), as a less toxic adjuvant than CT. LT(R192G) was as effective as or more effective than CT at inducing a mucosal CTL response. Moreover, LT(R192G) was as effective without IL-12 as CT was when combined with IL-12, and the response elicited by LT(R192G) with the vaccine was not further enhanced by the addition of IL-12. GM-CSF synergized with LT(R192G) without exogenous IL-12. Therefore, LT(R192G) may induce a more favorable cytokine response by not inhibiting IL-12 production. In particular, less IL-4 is made after LT(R192G) than CT immunization, and the response is less ...

Competitive Inhibition In Vivo and Skewing of the T Cell Repertoire of Antigen-Specific CTL Priming by an Anti-Peptide-MHC Monoclonal Antibody

The Journal of Immunology, 2001

We have recently described a mAb, KP15, directed against the MHC-I/peptide molecular complex cons... more We have recently described a mAb, KP15, directed against the MHC-I/peptide molecular complex consisting of H-2Dd and a decamer peptide corresponding to residues 311–320 of the HIV IIIB envelope glycoprotein gp160. When administered at the time of primary immunization with a vaccinia virus vector encoding gp160, the mAb blocks the subsequent appearance of CD8+ CTL with specificity for the immunodominant Ag, P18-I10, presented by H-2Dd. This inhibition is specific for this particular peptide Ag; another H-2Dd-restricted gp160 encoded epitope from a different HIV strain is not affected, and an H-2Ld-restricted epitope encoded by the viral vector is also not affected. Using functional assays and specific immunofluorescent staining with multivalent, labeled H-2Dd/P18-I10 complexes (tetramers), we have enumerated the effects of blocking of priming on the subsequent appearance, avidity, and TCR Vβ usage of Ag-specific CTL. Ab blocking skews the proportion of high avidity cells emerging fro...

A Novel Functional CTL Avidity/Activity Compartmentalization to the Site of Mucosal Immunization Contributes to Protection of Macaques against Simian/Human Immunodeficiency Viral Depletion of Mucosal CD4+ T Cells

The Journal of Immunology, 2007

The presence of high-avidity CTLs in the right compartment can greatly affect clearance of a viru... more The presence of high-avidity CTLs in the right compartment can greatly affect clearance of a virus infection (for example, AIDS viral infection of and dissemination from mucosa). Comparing mucosal vs systemic immunization, we observed a novel compartmentalization of CTL avidity and proportion of functionally active Ag-specific CD8+ T cells to tissues proximal to sites of immunization. Whereas both s.c. and intrarectal routes of immunization induced tetramer+ cells in the spleen and gut, the mucosal vaccine induced a higher percentage of functioning IFN-γ+ Ag-specific CD8+ T cells in the gut mucosa in mice. Translating to the CD8+ CTL avidity distribution in rhesus macaques, intrarectal vaccination induced more high-avidity mucosal CTL than s.c. vaccination and protection of mucosal CD4+ T cells from AIDS viral depletion, whereas systemic immunization induced higher avidity IFN-γ-secreting cells in the draining lymph nodes but no protection of mucosal CD4+ T cells, after mucosal chal...

IL-15 Expands Unconventional CD8ααNK1.1+ T Cells but Not Vα14Jα18+ NKT Cells

The Journal of Immunology, 2008

Despite recent gains in knowledge regarding CD1d-restricted NKT cells, very little is understood ... more Despite recent gains in knowledge regarding CD1d-restricted NKT cells, very little is understood of non-CD1d-restricted NKT cells such as CD8+NK1.1+ T cells, in part because of the very small proportion of these cells in the periphery. In this study we took advantage of the high number of CD8+NK1.1+ T cells in IL-15-transgenic mice to characterize this T cell population. In the IL-15-transgenic mice, the absolute number of CD1d-tetramer+ NKT cells did not increase, although IL-15 has been shown to play a critical role in the development and expansion of these cells. The CD8+NK1.1+ T cells in the IL-15-transgenic mice did not react with CD1d-tetramer. Approximately 50% of CD8+NK1.1+ T cells were CD8αα. In contrast to CD4+NK1.1+ T cells, which were mostly CD1d-restricted NKT cells and of which ∼70% were CD69+CD44+, ∼70% of CD8+NK1.1+ T cells were CD69−CD44+. We could also expand similar CD8ααNK1.1+ T cells but not CD4+ NKT cells from CD8α+β− bone marrow cells cultured ex vivo with IL-...

The Murine Kupffer Cell

Journal of Immunology, Dec 1, 1979

Murine Kupffer cells, the tissue macrohages of the liver, were isolated by collagenase digestion,... more Murine Kupffer cells, the tissue macrohages of the liver, were isolated by collagenase digestion, differential sedimentation over Metrizamide, and glass adherence. The resultant cell population was more than 86% phagocytic, and 95% of cell stained positively for α-naphtyl butyratc esterase activity. The cells also had cell surface receptors for complement (C) and the Fc portion of IgG. In additon, a large proportion of Kupffer cells was shown to bear Ia antigens: about half of the cells bore I-A subregion-encoded antigens. Kupffer cell populations were capable of reconstituting antigen-stumulated proliferative responses of antigen-primed, macrophage-depleted, lymph node T cells. The ability to reconstitute proliferation was enriched in the adheren population and was resistant to radiation and treatment with an anti-Thy antiserum and C. We conclude that isolated murine Kupffer cells bear the Ia phenotype of accessory cells that function in antigen presentation and that Kupffer cells can paricipate in the induction of antigen-specific immune responses. These data suggest that Kupffer cells may play a role in modulating responses to enterically derived antigens.

This article cites 22 articles, 7 of which can be accessed free at:

Abstract LB-A06: Pipeline for High Throughput Analysis of Exosomes in Clinical Biofluids

Molecular Cancer Therapeutics, 2018

Purpose/Objective(s): Because Extracellular Vesicles (EVs) carry surface receptors that are chara... more Purpose/Objective(s): Because Extracellular Vesicles (EVs) carry surface receptors that are characteristic of their cells of origin, EVs have tremendous potential as non-invasive biomarkers for diagnosis, risk-stratification, treatment selection, and treatment monitoring. We developed a first-in-class pipeline to characterize EV heterogeneity and provide high-sensitivity quantification of informative EVs in biofluids before, during, and after treatment. By combining multiplex assays with high-resolution, single EV flow cytometric methods together into a Mutiplex-to-Single EV Analysis (Mt-SEA) pipeline, we are able to characterize a broad range of relevant EV subsets, while also accurately measuring the concentration of specific EV populations. Exploratory studies presented here validate the performance of Mt-SEA method by confirming strong correlations of liquid biopsy EV repertoires with tumor burden and responses to treatment. Furthermore, EV analysis with Mt-SEA may identify prev...

Effects of Cross-Presentation, Antigen Processing, and Peptide Binding in HIV Evasion of T Cell Immunity

Journal of immunology (Baltimore, Md. : 1950), 2018

Unlike cytosolic processing and presentation of viral Ags by virus-infected cells, Ags first expr... more Unlike cytosolic processing and presentation of viral Ags by virus-infected cells, Ags first expressed in infected nonprofessional APCs, such as CD4T cells in the case of HIV, are taken up by dendritic cells and cross-presented. This generally requires entry through the endocytic pathway, where endosomal proteases have first access for processing. Thus, understanding virus escape during cross-presentation requires an understanding of resistance to endosomal proteases, such as cathepsin S (CatS). We have modified HIV-1gp120 by mutating a key CatS cleavage site (ThrThr) in the V3 loop of the immunodominant epitope IGPGRAFYto IGPGRAFYto prevent digestion. We found this mutation to facilitate cross-presentation and provide evidence from MHC binding and X-ray crystallographic structural studies that this results from preservation of the epitope rather than an increased epitope affinity for the MHC class I molecule. In contrast, when the protein is expressed by a vaccinia virus in the cyt...

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Journal of immunology (Baltimore, Md. : 1950), May 1, 2017

T cells with high functional avidity can sense and respond to low levels of cognate Ag, a charact... more T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high-avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that v...

Recombinant vaccine viruses expressing IL-15 and methods using the same

Treatment of cancer via targeting of il-13 receptor-alpha2

Mucosal Cytotoxic T Lymphocyte Responses

Mucosal cytotoxic T lymphocyte responses

Overcoming CD4 deficiency to induce long-lived memory CD8+ CTL

Retrovirology, 2006

Human retroviruses and AIDS 1994

More detailed tables of contents are to be found within the various parts of the compendium. The ... more

Human retroviruses and AIDS, 1991. [CONTAINS GLOSSARY]

Thin repurIwevpcwmred eamvncarunlwfwvxh qanmurwdbymr~rwy Mlhc[JnlWd.S!mm Owerrrmcnt. Nciikrthc (J... more Thin repurIwevpcwmred eamvncarunlwfwvxh qanmurwdbymr~rwy Mlhc[JnlWd.S!mm Owerrrmcnt. Nciikrthc (Jnitd Slalm(h~rnmnl mcnnyngwrxy thcmvf, nvrcmryd Ihwlr cmployea, m-kc mIy wnrranly, csprcas ur lmpikvl, or uaurna qny la~l Iidklily tw rcepmci. hdily hw Ihe wtxmcy, uornplaeneu, IW udulneca of wry mhmvrmvm Wwrmlm tiwlt w prvwam didvnad, or rcprcmnl~thnl iis uu WIWAI w mfrin~wwntdy owned ri~hl~. Mar. crwe krcin m my vpmMiu wnmcrcml pdud, pwcna, of wrvww hy Irdc mne, lredenmrl, mmdedurer, IU dkrwmc dIEm m~naucaamrilyccmIIIuIc O; mrply IIS cndummcnl, wm. rrvand-lntn, or [morms hy he 1Mml .SYalcs( ivwcrnmcrvl or qny -gcnuy lhcrd. "Ilrc vicwn d wpmanrn d dwws cqwaced hcrwm do rmi nvttsmrily fimc Or rctld thi~wf Ihe [Jnild Shlen (bvcrnrrwnl wr any ~ncy lhcmL osAhrinlm LosAlar,IOSNational Laboratory lmsAlamos,New Mexico 87545 HUMAN RETROVIRUSES and AIDS 1991 A COMPILATION AND ANALYSIS OF NUCLEIC ACID

Comparative analysis of SIV-specific cellular immune responses induced by different vaccine platforms in rhesus macaques

Clinical Immunology, 2014

To identify the most promising vaccine candidates for combinatorial strategies, we compared five ... more

Humoral immunity induced by mucosal and/or systemic SIV-specific vaccine platforms suggests novel combinatorial approaches for enhancing responses

Clinical Immunology, 2014

Combinatorial HIV/SIV vaccine approaches targeting multiple arms of the immune system might impro... more Combinatorial HIV/SIV vaccine approaches targeting multiple arms of the immune system might improve protective efficacy. We compared SIV-specific humoral immunity induced in rhesus macaques by five vaccine regimens. Systemic regimens included ALVAC-SIVenv priming and Env boosting (ALVAC/Env); DNA immunization; and DNA plus Env co-immunization (DNA&Env). RepAd/Env combined mucosal replication-competent Ad-env priming with

TLR agonists and/or IL-15 adjuvanted mucosal SIV vaccine reduced gut CD4+ memory T cell loss in SIVmac251-challenged rhesus macaques

Vaccine, 2011

Adjuvant plays an important role in increasing and directing vaccine-induced immune responses. In... more Adjuvant plays an important role in increasing and directing vaccine-induced immune responses. In a previous study, we found that a mucosal SIV vaccine using a combination of IL-15 and TLR agonists as adjuvant mediated partial protection against SIVmac251 rectal challenge, whereas neither IL-15 nor TLR agonists alone as an adjuvant impacted the plasma viral loads. In this study, dissociation of CD4 + T cell preservation with viral loads was observed in the animals vaccinated with adjuvants. Significantly higher levels of memory CD4 + T cell numbers were preserved after SIVmac251 infection in the colons of the animals vaccinated with vaccine containing any of these adjuvants compared to no adjuvant. When we measured the viral-specific CD8 + tetramer responses in the colon lamina propria, we found significantly higher levels of gag, tat, and pol epitope tetramer + T cell responses in these animals compared to ones without adjuvant, even if some of the animals had similarly high viral loads. Furthermore, this CD4 + T preservation was positively correlated with increased levels of gag and Tat, but not pol tetramer + T cell responses, and inversely correlated with beta-chemokine expression. The pre-challenged APOBEC3G expression level, which has previously been shown inversely associated with viral loads, was further found positively correlated with CD4 + T cell number preservation. Overall, these data highlight one unrecognized role of adjuvant in HIV vaccine development, and show that vaccines can produce a surprising discordance between CD4 + T cell levels and SIV viral load.

Antibodies Directed Against the MHC-I Molecule H-2Dd Complexed with an Antigenic Peptide: Similarities to a T Cell Receptor with the Same Specificity

The Journal of Immunology, 2000

αβ TCRs, which use an Ab-like structure to form a combining site, recognize molecular complexes c... more αβ TCRs, which use an Ab-like structure to form a combining site, recognize molecular complexes consisting of peptides bound to MHC class I (MHC-I) or class II (MHC-II) molecules. To explore the similarities and differences between Ab and T cell recognition of similar structures, we have isolated two mAbs, KP14 and KP15, that specifically bind H-2Dd complexed with an HIV envelope gp160-derived peptide, P18-I10. These Abs are MHC and peptide specific. Fine specificity of mAb binding was analyzed using a panel of synthetic peptides, revealing similarities between the mAb and a cloned TCR with the same specificity. These two mAbs used the same VH and JH gene segments, but different D, Vκ, and Jκ genes. Administered in vivo, mAb KP15 blocked the induction of CTL specific for recombinant vaccinia virus-encoded gp160, indicating its ability to bind endogenously generated MHC/peptide complexes. Analysis of the fine specificity of these mAbs in the context of their encoded amino acid sequen...

Interplay of Cytokines and Adjuvants in the Regulation of Mucosal and Systemic HIV-Specific CTL

The Journal of Immunology, 2000

We examined the interplay between cytokines and adjuvants to optimize the induction of CTL by a m... more We examined the interplay between cytokines and adjuvants to optimize the induction of CTL by a mucosal HIV peptide vaccine. We show synergy between IL-12 and GM-CSF when administered together with the HIV peptide PCLUS3–18IIIB and cholera toxin (CT) in the induction of CTL activity and protection against mucosal viral transmission. Further, we examine the efficacy of mutant Escherichia coli labile toxin, LT(R192G), as a less toxic adjuvant than CT. LT(R192G) was as effective as or more effective than CT at inducing a mucosal CTL response. Moreover, LT(R192G) was as effective without IL-12 as CT was when combined with IL-12, and the response elicited by LT(R192G) with the vaccine was not further enhanced by the addition of IL-12. GM-CSF synergized with LT(R192G) without exogenous IL-12. Therefore, LT(R192G) may induce a more favorable cytokine response by not inhibiting IL-12 production. In particular, less IL-4 is made after LT(R192G) than CT immunization, and the response is less ...

Competitive Inhibition In Vivo and Skewing of the T Cell Repertoire of Antigen-Specific CTL Priming by an Anti-Peptide-MHC Monoclonal Antibody

The Journal of Immunology, 2001

We have recently described a mAb, KP15, directed against the MHC-I/peptide molecular complex cons... more We have recently described a mAb, KP15, directed against the MHC-I/peptide molecular complex consisting of H-2Dd and a decamer peptide corresponding to residues 311–320 of the HIV IIIB envelope glycoprotein gp160. When administered at the time of primary immunization with a vaccinia virus vector encoding gp160, the mAb blocks the subsequent appearance of CD8+ CTL with specificity for the immunodominant Ag, P18-I10, presented by H-2Dd. This inhibition is specific for this particular peptide Ag; another H-2Dd-restricted gp160 encoded epitope from a different HIV strain is not affected, and an H-2Ld-restricted epitope encoded by the viral vector is also not affected. Using functional assays and specific immunofluorescent staining with multivalent, labeled H-2Dd/P18-I10 complexes (tetramers), we have enumerated the effects of blocking of priming on the subsequent appearance, avidity, and TCR Vβ usage of Ag-specific CTL. Ab blocking skews the proportion of high avidity cells emerging fro...

A Novel Functional CTL Avidity/Activity Compartmentalization to the Site of Mucosal Immunization Contributes to Protection of Macaques against Simian/Human Immunodeficiency Viral Depletion of Mucosal CD4+ T Cells

The Journal of Immunology, 2007

The presence of high-avidity CTLs in the right compartment can greatly affect clearance of a viru... more The presence of high-avidity CTLs in the right compartment can greatly affect clearance of a virus infection (for example, AIDS viral infection of and dissemination from mucosa). Comparing mucosal vs systemic immunization, we observed a novel compartmentalization of CTL avidity and proportion of functionally active Ag-specific CD8+ T cells to tissues proximal to sites of immunization. Whereas both s.c. and intrarectal routes of immunization induced tetramer+ cells in the spleen and gut, the mucosal vaccine induced a higher percentage of functioning IFN-γ+ Ag-specific CD8+ T cells in the gut mucosa in mice. Translating to the CD8+ CTL avidity distribution in rhesus macaques, intrarectal vaccination induced more high-avidity mucosal CTL than s.c. vaccination and protection of mucosal CD4+ T cells from AIDS viral depletion, whereas systemic immunization induced higher avidity IFN-γ-secreting cells in the draining lymph nodes but no protection of mucosal CD4+ T cells, after mucosal chal...

IL-15 Expands Unconventional CD8ααNK1.1+ T Cells but Not Vα14Jα18+ NKT Cells

The Journal of Immunology, 2008

Despite recent gains in knowledge regarding CD1d-restricted NKT cells, very little is understood ... more Despite recent gains in knowledge regarding CD1d-restricted NKT cells, very little is understood of non-CD1d-restricted NKT cells such as CD8+NK1.1+ T cells, in part because of the very small proportion of these cells in the periphery. In this study we took advantage of the high number of CD8+NK1.1+ T cells in IL-15-transgenic mice to characterize this T cell population. In the IL-15-transgenic mice, the absolute number of CD1d-tetramer+ NKT cells did not increase, although IL-15 has been shown to play a critical role in the development and expansion of these cells. The CD8+NK1.1+ T cells in the IL-15-transgenic mice did not react with CD1d-tetramer. Approximately 50% of CD8+NK1.1+ T cells were CD8αα. In contrast to CD4+NK1.1+ T cells, which were mostly CD1d-restricted NKT cells and of which ∼70% were CD69+CD44+, ∼70% of CD8+NK1.1+ T cells were CD69−CD44+. We could also expand similar CD8ααNK1.1+ T cells but not CD4+ NKT cells from CD8α+β− bone marrow cells cultured ex vivo with IL-...