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  • 1
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    Online Resource
    Host Factor Transcriptional Regulation Contributes to Preferential Expression of HIV Type 1 in IL-4–Producing CD4 T Cells
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 189, No. 6 ( 2012-09-15), p. 2746-2757
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 189, No. 6 ( 2012-09-15), p. 2746-2757
    Abstract: HIV type 1 (HIV-1) replicates preferentially in IL-4–producing CD4 T cells for unclear reasons. We show increased HIV-1 expression is irrespective of viral tropism for chemokine receptors as previously suggested, but rather transcription of the HIV-1 long terminal repeat (LTR) is increased in IL-4–producing CD4 T cells. Increased expression of HIV-1 message is also confirmed in IL-4–producing CD4 T cells from HIV-1–infected individuals ex vivo. In exploring a transcriptional mechanism, we identify a novel c-maf (required for IL-4 expression) transcription factor binding site just upstream of the dual NF-κB/NFAT binding sites in the proximal HIV-1 LTR. We demonstrate that c-maf binds this site in vivo and synergistically augments HIV-1 transcription in cooperation with NFAT2 and NF-κB p65, but not NFAT1 or NF-κB p50. Conversely, small interfering RNA inhibition of c-maf reduces HIV-1 transcription in IL-4–producing T cells. Thus, c-maf increases HIV-1 expression in IL-4–producing CD4 T cells by binding the proximal HIV-1 LTR and augmenting HIV-1 transcription in partnership with NFAT2 and NF-κB p65 specifically. This has important implications for selective targeting of transcription factors during HIV-1 infection because, over the course of HIV-1 progression/AIDS, IL-4–producing T cells frequently predominate and substantially contribute to disease pathology.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1103129
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
    detail.hit.zdb_id: 1475085-5
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  • 2
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    Online Resource
    Breast Milk-Derived Antigen-Specific CD8+ T Cells: An Extralymphoid Effector Memory Cell Population in Humans
    The American Association of Immunologists ; 2005
    In:  The Journal of Immunology Vol. 174, No. 5 ( 2005-03-01), p. 2951-2956
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 174, No. 5 ( 2005-03-01), p. 2951-2956
    Abstract: Although mouse studies have demonstrated the presence of an effector memory population in nonlymphoid tissues, the phenotype of human CD8+ T cells present in such compartments has not been characterized. Because of the relatively large number of CD8+ T cells present in breast milk, we were able to characterize the phenotype of this cell population in HIV-infected and uninfected lactating women. CMV, influenza virus, EBV, and HIV-specific CD8+ T cells as measured by the IFN-γ ELISPOT and MHC class I tetramer staining were all present at greater frequencies in breast milk as compared with blood. Furthermore, a greater percentage of the breast milk CD8+ T cells expressed the intestinal homing receptor, CD103, and the mucosal homing receptor CCR9. Breast milk T cells were predominantly CD45RO+HLADR+ and expressed low levels of CD45RA, CD62L, and CCR7 consistent with an effector memory population. Conversely, T cells derived from blood were mainly characterized as central memory cells (CCR7+CD62L+). These results demonstrate a population of extralymphoid CD8+ T cells with an effector memory phenotype in humans, which could contribute to enhanced local virologic control and the relative lack of HIV transmission via this route.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.174.5.2951
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2005
    detail.hit.zdb_id: 1475085-5
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  • 3
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    Online Resource
    The tetraspanin CD151 is an activation molecule that characterizes M. tuberculosis - specific effector CD4+ T cells
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 65.9-65.9
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 65.9-65.9
    Abstract: Tetraspanins are a family of membrane proteins regulating cell morphology, motility, fusion, and signaling. CD151 is expressed on T cells that stabilizes the immune synapse during antigen recognition, engages in integrin signaling, and primes T cell activation. We have recently demonstrated that CD151 expression leads to increased proliferation and activation in human CD4+ T cells. Given its important functional role, we hypothesized that CD151 may be elevated on M. tb-specific effector CD4+ T cells. We assessed CD151 on ex vivo PBMCs from PPD+ donors (Purified Protein Derivative from M. tb) stimulated with M. tb H37Rv whole cell lysate. CD151+ frequencies were elevated on IFN-γ+ (52 ± 6% vs. 17 ± 2%, P & lt;0.001) and TNF-α+ (74 ± 6% vs. 17 ± 2%, P & lt;0.0001) CD4+ T cells compared to overall baseline levels. To assess the functionality of CD151 on M. tb-specific CD4+ T cells, we established an ex vivo culture model with M. tb-infected monocyte-derived macrophages (MDMs) in the presence of autologous PPD+ or PPD− donor CD4+ T cells. Upon day 6 of culture, PPD+ donor cultures, proliferating Ki67+ CD4+T cells were elevated in CD151 and CD25, but diminished in CD57, cell surface expression. Additionally, enhanced frequencies of CD151+ Ki67+CD4+T cells were associated with reduced M. tb growth within autologous MDMs during ex vivo culture. In summary, CD151 is a novel T cell activation marker that is elevated on M. tb- specific CD4+ T cells, and is associated with diminished M. tb growth in culture. CD151 could thus be an interesting candidate to supplement the existing TB-TAM diagnostic (T cell activation marker of tuberculosis) – the first to assess the quality of the CD4+ effector T-cell response to M. tb – and may guide future CD4+ T-cell based vaccine strategies.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.65.9
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 4
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    Adapted HIV-1 epitopes can elicit functional CD8+ T cell responses (P6177)
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 190, No. 1_Supplement ( 2013-05-01), p. 118.12-118.12
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 190, No. 1_Supplement ( 2013-05-01), p. 118.12-118.12
    Abstract: HIV readily mutates and many of these mutations can be predicted based on the human leukocyte antigen class I (HLA-I) allele of the infected individual. Majority of these HLA-associated HIV polymorphisms may represent escape mutations whereby the epitope adapts to HLA-restricted pressure in every individual. Though these adapted epitopes have escaped recognition by some CD8 T cells, others may readily recognize them. However, to truly answer the question as to whether adapted epitopes induce CD8 T cell responses (primary response), acutely infected patient samples must be tested where we can accurately predict the infecting viral strain. We therefore tested whether CD8 T cells are induced when presented with either adapted or non-adapted epitopes encoded by the infecting viral strain in 8 HIV+ acute patients. Primary responses were more likely induced to non-adapted epitopes compared to the adapted (p=0.041). Furthermore, the few adapted epitopes that were able to elicit responses (primary or not) were predicted to exhibit a significantly higher HLA binding affinity compared to ones that did not elicit a response. CD8 T cells responding to adapted epitopes also shared similar magnitude, functional avidity, and polyfunctionality compared to those elicited to the non-adapted. Our results suggest at least some epitopes with HLA-associated mutations are still potentially immunogenic and may have important implications for T cell-based vaccine development.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.190.Supp.118.12
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
    detail.hit.zdb_id: 1475085-5
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  • 5
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    Online Resource
    Antisense transcript derived HIV-1 cryptic epitopes are recognized by T cells during chronic infection.
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 148.10-148.10
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 148.10-148.10
    Abstract: Alternative reading frames (ARF) of HIV, both sense and antisense directions, have shown to produce polypeptides of unknown functions. Although the roles of these polypeptides are unclear, they can still potentially act as HIV derived antigens, eliciting host T cell responses. These ARF derived epitopes, known as cryptic epitopes (CE), occur commonly in HIV, SIV, and other retroviruses through ribosomal frame-shifting, internal ribosomal entry sites, and alternative start codon initiation. We hypothesize that T cell responses to CE are capable of driving viral escape mutations at a population level. In order to identify CE of HIV capable of driving viral escape, sequence changes in gag, pol, and nef of HIV were identified during acute infection in a cohort of Zambian serodiscordant couples. HLA-I associated polymorphisms in ARF can thus be identified, predicting potentially immunogenic CE. Several CE were identified as a result (N=66), in which the majority appears to have been derived from antisense ARF. These CE were used to stimulate cryopreserved PBMC samples from HIV-1 patients in the chronic stage of infection. We found 8/32 patients responded to at least one predicted CE as shown by IFNγ ELISpot. Interestingly, all 10 immunogenic CEs found in this study were derived from a single antisense reading frame in the pol coding region. Furthermore, these CE were not only capable of eliciting CD8, but also CD4 responses. When examining alternative start codons in each reading frame, we found an enrichment of CUG in the antisense frame containing the immunogenic CE. Together, our results show HIV antisense CE can be targeted by T cells and may therefore have implications for T-cell vaccines.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.148.10
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 6
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    HIV-1–Specific CD8 T Cells Exhibit Limited Cross-Reactivity during Acute Infection
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 8 ( 2016-04-15), p. 3276-3286
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 8 ( 2016-04-15), p. 3276-3286
    Abstract: Prior work has demonstrated that HIV-1–specific CD8 T cells can cross-recognize variant epitopes. However, most of these studies were performed in the context of chronic infection, where the presence of viral quasispecies makes it difficult to ascertain the true nature of the original antigenic stimulus. To overcome this limitation, we evaluated the extent of CD8 T cell cross-reactivity in patients with acute HIV-1 clade B infection. In each case, we determined the transmitted founder virus sequence to identify the autologous epitopes restricted by individual HLA class I molecules. Our data show that cross-reactive CD8 T cells are infrequent during the acute phase of HIV-1 infection. Moreover, in the uncommon instances where cross-reactive responses were detected, the variant epitopes were poorly recognized in cytotoxicity assays. Molecular analysis revealed that similar antigenic structures could be cross-recognized by identical CD8 T cell clonotypes mobilized in vivo, yet even subtle differences in a single TCR-accessible peptide residue were sufficient to disrupt variant-specific reactivity. These findings demonstrate that CD8 T cells are highly specific for autologous epitopes during acute HIV-1 infection. Polyvalent vaccines may therefore be required to provide optimal immune cover against this genetically labile pathogen.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1502411
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
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  • 7
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    Characterization of T cell responses to cryptic epitopes in recipients of a non-codon optimized HIV-1 vaccine (P4495)
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 190, No. 1_Supplement ( 2013-05-01), p. 179.10-179.10
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 190, No. 1_Supplement ( 2013-05-01), p. 179.10-179.10
    Abstract: Cryptic epitopes (CE) are MHC-I-restricted peptides encoded by any of the 5 alternative reading frames (ARFs) of a gene. CE-specific T cells (Tc) have previously been detected in HIV-1 infected patients but whether responses to CE can be induced by vaccination is currently unknown. Our previous work demonstrated that vaccination with naturally-encoded, non-codon optimized vectors generate CE more frequently than codon-optimized vectors. We therefore analyzed samples from 126 individuals who received either a naturally-encoded MVA/HIV62 double prime-double boost regimen (vaccine) or saline (placebo) during the HVTN205 trial. Peripheral blood mononuclear cells collected at 2 weeks post final vaccination were stimulated in an IFNγ ELISpot assay with overlapping peptide pools (OLPs) for HIV-1 Gag, Pol, and all 5 ARFs of these regions. Vaccinees had significantly more positive responses toward Gag but not Pol than placebo recipients (p=0.020, Mann-Whitney U test). Ex vivo Tc responses to potential CE were low in magnitude and their frequency did not differ significantly between treatment groups. In a cultured assay however, the median magnitude of responses to ARF OLP subpools was significantly greater in vaccinees (p & lt; 0.001, Mann-Whitney U test), indicating CE-specific Tc responses are present but below the IFNγ ELISpot assay’s limit of detection. Thus, we recommend that future vaccines expand the breadth of HIV-1 Tc responses through designs that preserve naturally-encoded CE.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.190.Supp.179.10
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
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  • 8
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    CD151 Expression Is Associated with a Hyperproliferative T Cell Phenotype
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 199, No. 9 ( 2017-11-01), p. 3336-3347
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 199, No. 9 ( 2017-11-01), p. 3336-3347
    Abstract: The tetraspanin CD151 is a marker of aggressive cell proliferation and invasiveness for a variety of cancer types. Given reports of CD151 expression on T cells, we explored whether CD151 would mark T cells in a hyperactivated state. Consistent with the idea that CD151 could mark a phenotypically distinct T cell subset, it was not uniformly expressed on T cells. CD151 expression frequency was a function of the T cell lineage (CD8 & gt; CD4) and a function of the memory differentiation state (naive T cells & lt; central memory T cells & lt; effector memory T cells & lt; T effector memory RA+ cells). CD151 and CD57, a senescence marker, defined the same CD28− T cell populations. However, CD151 also marked a substantial CD28+ T cell population that was not marked by CD57. Kinome array analysis demonstrated that CD28+CD151+ T cells form a subpopulation with a distinct molecular baseline and activation phenotype. Network analysis of these data revealed that cell cycle control and cell death were the most altered process motifs in CD28+CD151+ T cells. We demonstrate that CD151 in T cells is not a passive marker, but actively changed the cell cycle control and cell death process motifs of T cells. Consistent with these data, long-term T cell culture experiments in the presence of only IL-2 demonstrated that independent of their CD28 expression status, CD151+ T cells, but not CD151− T cells, would exhibit an Ag-independent, hyperresponsive proliferation phenotype. Not unlike its reported function as a tumor aggressiveness marker, CD151 in humans thus marks and enables hyperproliferative T cells.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1700648
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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  • 9
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    The tetraspanin CD151 is elevated on activated human CD4+ T cells with enhanced cytotoxic potential
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 119.11-119.11
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 119.11-119.11
    Abstract: Circulating cytotoxic CD4+ T cells are absent in healthy individuals, but have been reported in autoimmune and inflammatory states. Cytotoxic CD4+ T cells arise largely as a result of chronic viral infection, such as CMV. These cells are characterized by the loss of CD28/CD27, their memory differentiation status (TEM/EMRA), and a phenotype primed towards the targeting of viral antigens. While cytotoxic CD4+ T cells are speculated to complement cytotoxic CD8+ T cell activity, they may also contribute to MHC class II-directed immunopathogenic states (e.g., vascular complications resulting from endothelia damage). The molecular mechanism of how cytotoxic CD4+ T cells are propagated remains elusive. Recently, tetraspanins have been shown to influence the cytotoxic potential of immune cells- CD63 aids in mast cell degranulation whereas CD53 modulates NK cell cytotoxicity. Here, we report that the tetraspanin CD151 is elevated on circulating CD4+ T cells with enhanced cytotoxic potential. We observed that CD151+ frequencies were most elevated on CD28neg and TEM/TEMRA CD4+ T cells. Importantly, CD151+ frequencies were robustly enriched on CD4+ T cells containing preformed granzyme B (GzmB) (51 ± 18% vs. 14 ± 6%)- cell populations reported as elevated after primary CMV infection. Within CMV-seropositive donors, CD151+ frequencies were robustly enriched on IFN-γ+GzmB+ CD4+ T cells responding to overlapping peptides from CMV pp65 (60 ± 21% vs. 17 ± 8% baseline). In summary, the tetraspanin CD151 is a cell surface molecule that demarcates circulating CD4+ T cells with enhanced cytotoxic potential, particularly against CMV antigen. Tetraspanins may therefore be a class of molecules that tunes the effector cell response to persistent antigens.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.119.11
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 10
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    Single-cell cloning of untreated HIV-specific natural killer cells in humans
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 76.4-76.4
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 76.4-76.4
    Abstract: Beyond their ability to eliminate infected cells without the need for prior sensitization, natural killer (NK) cells have been shown to exhibit adaptive immune functions. In particular, our lab demonstrated that antigen-specific memory NK cells responses against SIV can be induced by infection and vaccination in non-human primates. These data suggested that a subset of NK cells in humans may also mediate immunological memory responses to HIV. To study human HIV-antigen-specific NK cells in more detail, we adapted limiting dilution assays to clonally expand individual peripheral blood NK cells (NKCL) from untreated HIV-infected individuals. Using a calcein acetoxymethyl ester cytotoxicity assay, the ability of each NKCL to lyse MHC-devoid K562 cell lines or autologous B-LCLs pulsed with a pool of MOG- (human self-peptide), HIV Gag- or HIV Env-derived overlapping peptides was assessed. As expected, all tested NKCL could potently lyse K562 cells (median=56% killing) but did not kill B-LCL pulsed with the MOG control. Strikingly, 37.5% of NKCL displayed anti-HIV Gag cytotoxic activity up to 31% specific lysis (range: 1%–31%), while 25% of NKCL displayed anti-HIV Env cytotoxic activity up to 72% specific lysis (range: 1%–72%). Furthermore, pre-treatment with an anti-NKG2C blocking antibody decreased the specific lysis, thereby confirming the importance of NKG2C receptor in the function of antigen-specific NK cells. Thus, we were able to isolate single NK cells displaying potent HIV-specific killing, within the range of robust cytotoxicity normally found against tumor cells. Together these data suggest that HIV-specific responses mediated by NK cells exist in humans and may have the potential to be harnessed for therapeutic modalities.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.76.4
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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