scholarly journals Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy

2020 ◽  
Author(s):  
Marieke Verweij ◽  
Scott G. Hansen ◽  
Ravi Iyer ◽  
Nessy John ◽  
Daniel Malouli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccine Efficacy ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Functional Differentiation ◽  
Peptide Epitopes ◽  
Mhc Ii ◽  
Cell Responses ◽  
Infected Cells

AbstractStrain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells that recognize peptide epitopes presented by major histocompatibility complex (MHC)-II and MHC-E molecules, instead of MHC-Ia, and are uniquely able to mediate stringent control and subsequent clearance of highly pathogenic SIV in ∼50% of vaccinated rhesus macaques (RMs). We show that the MHC-E ligand VMAPRTLLL (VL9), encoded by the Rh67 gene (or its HCMV UL40 counterpart) is required for recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8+ T cells via its ability to promote intracellular MHC-E transport. Moreover, deletion of Rh67 from 68-1 RhCMV/SIV vectors, or mutation of its embedded VL9 ligand, abrogated induction of MHC-E-restricted CD8+ T cell responses, leaving responses that exclusively target MHC-II-restricted epitopes. These MHC-II-presented CD8+ T cell responses, though comparable in response magnitude and functional differentiation to responses arising from the efficacious 68-1 vector, did not protect RMs against SIV challenge, indicating that Rh67/UL40-enabled direct priming of MHC-E-targeted CD8+ T cells is a crucial element of RhCMV/SIV vaccine efficacy.One Sentence SummaryA cytomegalovirus protein (Rh67/UL40) that upregulates MHC-E expression on RhCMV/SIV-vector infected cells is required for induction of MHC-E-restricted CD8+ T cells and for protection against SIV.

scholarly journals Cytomegaloviral determinants of CD8+ T cell programming and RhCMV/SIV vaccine efficacy

2020 ◽  
Author(s):  
Daniel Malouli ◽  
Scott G. Hansen ◽  
Meaghan H. Hancock ◽  
Colette M. Hughes ◽  
Julia C. Ford ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccine Efficacy ◽  
T Cell Responses ◽  
Functional Differentiation ◽  
T Cell Response ◽  
Alternative Response ◽  
Mhc Ii ◽  
Cell Responses ◽  
Human Cmv ◽  
Genomic Regions

AbstractSimian immunodeficiency virus (SIV) insert-expressing, 68-1 Rhesus Cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex (MHC)-E- and -II-restricted, SIV-specific CD8+ T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) has not been characterized. We demonstrate that these unconventional responses resulted from a chance genetic rearrangement in 68-1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions (Rh157.5/.4 and Rh158-161). Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)-derived sequences (UL128/130; UL146/147) leads to either of two distinct CD8+ T cell response types – MHC-Ia-restricted-only, or a mix of MHC-II- and MHC-Ia-restricted CD8+ T cells. Despite response magnitude and functional differentiation being similar to RhCMV 68-1, neither alternative response type mediated protection against SIV challenge. These findings implicate MHC-E-restricted CD8+ T cell responses as mediators of anti-SIV efficacy and indicate that translation of RhCMV/SIV vector efficacy to humans will likely require deletion of all the genes that inhibit these responses from the HCMV/HIV vector.One-sentence summaryEight genes in two spatially distinct RhCMV gene regions control induction of unconventionally restricted CD8+ T cell responses and the efficacy of RhCMV/SIV vaccine vectors against SIV challenge.

scholarly journals Cytomegaloviral determinants of CD8+ T cell programming and RhCMV/SIV vaccine efficacy

2021 ◽  
Vol 6 (57) ◽  
pp. eabg5413
Author(s):  
Daniel Malouli ◽  
Scott G. Hansen ◽  
Meaghan H. Hancock ◽  
Colette M. Hughes ◽  
Julia C. Ford ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccine Efficacy ◽  
T Cell Responses ◽  
Functional Differentiation ◽  
T Cell Response ◽  
Alternative Response ◽  
Mhc Ii ◽  
Cell Responses ◽  
Human Cmv ◽  
Genomic Regions

Simian immunodeficiency virus (SIV) insert–expressing, 68-1 rhesus cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex E (MHC-E)– and MHC-II–restricted, SIV-specific CD8+ T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) have not been characterized. We show that these unconventional responses resulted from a chance genetic rearrangement in 68-1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions (Rh157.5/Rh157.4 and Rh158-161), revealing three patterns of unconventional response inhibition. Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)–derived sequences (UL128/UL130; UL146/UL147) leads to either of two distinct CD8+ T cell response types—MHC-Ia–restricted only or a mix of MHC-II– and MHC-Ia–restricted CD8+ T cells. Response magnitude and functional differentiation are similar to RhCMV 68-1, but neither alternative response type mediated protection against SIV challenge. These findings implicate MHC-E–restricted CD8+ T cell responses as mediators of anti-SIV efficacy and indicate that translation of RhCMV/SIV vector efficacy to humans will likely require deletion of all genes that inhibit these responses from the HCMV/HIV vector.

scholarly journals Vaccinia-specific cytotoxic T-cell responses in the context of H-2 antigens not encountered in thymus may reflect aberrant recognition of a virus-H-2 complex.

1979 ◽  
Vol 149 (1) ◽  
pp. 150-157 ◽  
Author(s):  
P C Doherty ◽  
J C Bennink
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Antigen Complex ◽  
Infected Cells ◽  
Cytotoxic T Cell Responses

BALB/c (H-2Kd-Dd) spleen and lymph node populations were specifically depleted of alloreactive potential by filtration through H-2 different, irradiated recipients. These negatively selected T cells were then stimulated with vaccinia virus in mice expressing the foreign H-2 determinants encountered previously in the filter environment. Strong virus-immune cytotoxic T-cell responses were seen in the context of H-2Kk and H-2Ks, but not 2H-2Kb. The T cells generated were not cross-reactive for the H-2Kk and H-2Kd alleles, and responsiveness was independent of concurrent presence of effector populations operating at H-2D. These findings are consisent with the idea that recognition is mediated via a complex receptor, part of which is specific for virus and part for self H-2. The capacity to interact with allogeneic, virus-infected cells may then reflect aberrant recognition of a virus-H-2-antigen complex by this single, large binding site. For instance, the T cell which would normally recognize H-2Kd-virus x, or H-2Dd-minor histocompatibility antigen Z, may now show specificity for H-2Kk-vaccinia virus. Implications for both the selective role of the thymus and for mechanisms of tolerance are discussed.

scholarly journals Second Class Minors

2003 ◽  
Vol 197 (3) ◽  
pp. 375-385 ◽  
Author(s):  
Hiroeki Sahara ◽  
Nilabh Shastri
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Interleukin 4 ◽  
General Strategy ◽  
Mhc Ii ◽  
Cell Responses ◽  
Antigen Presenting

CD4 T cells regulate immune responses that cause chronic graft rejection and graft versus host disease but their target antigens remain virtually unknown. We developed a new method to identify CD4 T cell–stimulating antigens. LacZ-inducible CD4 T cells were used as a probe to detect their cognate peptide/MHC II ligand generated in dendritic cells fed with Escherichia coli expressing a library of target cell genes. The murine H46 locus on chromosome 7 was thus found to encode the interleukin 4–induced IL4i1 gene. The IL4i1 precursor contains the HAFVEAIPELQGHV peptide which is presented by Ab major histocompatibility complex class II molecule via an endogenous pathway in professional antigen presenting cells. Both allelic peptides bind Ab and a single alanine to methionine substitution at p2 defines nonself. These results reveal novel features of H loci that regulate CD4 T cell responses as well as provide a general strategy for identifying elusive antigens that elicit CD4 T cell responses to tumors or self-tissues in autoimmunity.

scholarly journals Reduced Protection from Simian Immunodeficiency Virus SIVmac251 Infection Afforded by Memory CD8+ T Cells Induced by Vaccination during CD4+ T-Cell Deficiency

2008 ◽  
Vol 82 (19) ◽  
pp. 9629-9638 ◽  
Author(s):  
Monica Vaccari ◽  
Joseph Mattapallil ◽  
Kaimei Song ◽  
Wen-Po Tsai ◽  
Anna Hryniewicz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Memory Cd8 T Cells ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus

ABSTRACT Adaptive CD4+ and CD8+ T-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication. Here, we have designed a study with Indian rhesus macaques to more directly assess the role of CD8 SIV-specific responses in control of viral replication. Macaques were immunized with a DNA prime-modified vaccinia virus Ankara (MVA)-SIV boost regimen under normal conditions or under conditions of antibody-induced CD4+ T-cell deficiency. Depletion of CD4+ cells was performed in the immunized macaques at the peak of SIV-specific CD4+ T-cell responses following the DNA prime dose. A group of naïve macaques was also treated with the anti-CD4 depleting antibody as a control, and an additional group of macaques immunized under normal conditions was depleted of CD8+ T cells prior to challenge exposure to SIVmac251. Analysis of the quality and quantity of vaccine-induced CD8+ T cells demonstrated that SIV-specific CD8+ T cells generated under conditions of CD4+ T-cell deficiency expressed low levels of Bcl-2 and interleukin-2 (IL-2), and plasma virus levels increased over time. Depletion of CD8+ T cells prior to challenge exposure abrogated vaccine-induced protection as previously shown. These data support the notion that adaptive CD4+ T cells are critical for the generation of effective CD8+ T-cell responses to SIV that, in turn, contribute to protection from AIDS. Importantly, they also suggest that long-term protection from disease will be afforded only by T-cell vaccines for HIV that provide a balanced induction of CD4+ and CD8+ T-cell responses and protect against early depletion of CD4+ T cells postinfection.

scholarly journals Bovine Immunoinhibitory Receptors Contribute to Suppression of Mycobacterium avium subsp. paratuberculosis-Specific T-Cell Responses

2015 ◽  
Vol 84 (1) ◽  
pp. 77-89 ◽  
Author(s):  
Tomohiro Okagawa ◽  
Satoru Konnai ◽  
Asami Nishimori ◽  
Ryoyo Ikebuchi ◽  
Seiko Mizorogi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Avium ◽  
T Cell Responses ◽  
T Cell Exhaustion ◽  
Content Type ◽  
Cell Exhaustion ◽  
Mhc Ii ◽  
Cell Responses ◽  
Ifn Γ

Johne's disease (paratuberculosis) is a chronic enteritis in cattle that is caused by intracellular infection withMycobacterium aviumsubsp.paratuberculosis. This infection is characterized by the functional exhaustion of T-cell responses toM. aviumsubsp.paratuberculosisantigens during late subclinical and clinical stages, presumably facilitating the persistence of this bacterium and the formation of clinical lesions. However, the mechanisms underlying T-cell exhaustion in Johne's disease are poorly understood. Thus, we performed expression and functional analyses of the immunoinhibitory molecules programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3)/major histocompatibility complex class II (MHC-II) inM. aviumsubsp.paratuberculosis-infected cattle during the late subclinical stage. Flow cytometric analyses revealed the upregulation of PD-1 and LAG-3 in T cells in infected animals, which suffered progressive suppression of interferon gamma (IFN-γ) responses to theM. aviumsubsp.paratuberculosisantigen. In addition, PD-L1 and MHC-II were expressed on macrophages from infected animals, consistent with PD-1 and LAG-3 pathways contributing to the suppression of IFN-γ responses during the subclinical stages ofM. aviumsubsp.paratuberculosisinfection. Furthermore, dual blockade of PD-L1 and LAG-3 enhancedM. aviumsubsp.paratuberculosis-specific IFN-γ responses in blood from infected animals, andin vitroLAG-3 blockade enhanced IFN-γ production fromM. aviumsubsp.paratuberculosis-specific CD4+and CD8+T cells. Taken together, the present data indicate thatM. aviumsubsp.paratuberculosis-specific T-cell exhaustion is in part mediated by PD-1/PD-L1 and LAG-3/MHC-II interactions and that LAG-3 is a molecular target for the control ofM. aviumsubsp.paratuberculosis-specific T-cell responses.

scholarly journals Major T Cell Response to a Mycolyl Glycolipid Is Mediated by CD1c Molecules in Rhesus Macaques

2012 ◽  
Vol 81 (1) ◽  
pp. 311-316 ◽  
Author(s):  
Daisuke Morita ◽  
Yuki Hattori ◽  
Takashi Nakamura ◽  
Tatsuhiko Igarashi ◽  
Hideyoshi Harashima ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rhesus Macaques ◽  
Acyl Chain ◽  
T Cell Responses ◽  
T Cell Response ◽  
Necrosis Factor Alpha ◽  
Mycolic Acids ◽  
Cell Responses

Human CD1b molecules contain a maze of hydrophobic pockets and a tunnel capable of accommodating the unusually long, branched acyl chain of mycolic acids, an essential fatty acid component of the cell wall of mycobacteria. It has been accepted that CD1b-bound mycolic acids constitute a scaffold for mycolate-containing (glyco)lipids stimulating CD1b-restricted T cells. Remarkable homology in amino acid sequence is observed between human and monkey CD1b molecules, and indeed, monkey CD1b molecules are able to bind glucose monomycolate (GMM), a glucosylated species of mycolic acids, and present it to specific human T cellsin vitro. Nevertheless, we found, unexpectedly, thatMycobacterium bovisbacillus Calmette-Guerin (BCG)-vaccinated monkeys exhibited GMM-specific T cell responses that were restricted by CD1c rather than CD1b molecules. GMM-specific, CD1c-restricted T cells were detected in the circulation of all 4 rhesus macaque monkeys tested after but not before vaccination with BCG. The circulating GMM-specific T cells were detected broadly in both CD4+and CD8+cell populations, and upon antigenic stimulation, a majority of the GMM-specific T cells produced both gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), two major host protective cytokines functioning against infection with mycobacteria. Furthermore, the GMM-specific T cells were able to extravasate and approach the site of infection where CD1c+cells accumulated. These observations indicate a previously inconceivable role for primate CD1c molecules in eliciting T cell responses to mycolate-containing antigens.

Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy

Immunity ◽  
2021 ◽  
Author(s):  
Amrita Bhattacharjee ◽  
Ansen H.P. Burr ◽  
Abigail E. Overacre-Delgoffe ◽  
Justin T. Tometich ◽  
Deyi Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Vaccine Efficacy ◽  
Oral Vaccine ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Environmental Enteric Dysfunction

scholarly journals Impact of Cytotoxic-T-Lymphocyte Memory Induction without Virus-Specific CD4+ T-Cell Help on Control of a Simian Immunodeficiency Virus Challenge in Rhesus Macaques

2009 ◽  
Vol 83 (18) ◽  
pp. 9339-9346 ◽  
Author(s):  
Tetsuo Tsukamoto ◽  
Akiko Takeda ◽  
Takuya Yamamoto ◽  
Hiroyuki Yamamoto ◽  
Miki Kawada ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic T Lymphocyte ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Cell Responses ◽  
Specific Memory ◽  
Immunodeficiency Virus ◽  
Virus Exposure ◽  
T Cell Help

ABSTRACT Despite many efforts to develop AIDS vaccines eliciting virus-specific T-cell responses, whether induction of these memory T cells by vaccination before human immunodeficiency virus (HIV) exposure can actually contribute to effective T-cell responses postinfection remains unclear. In particular, induction of HIV-specific memory CD4+ T cells may increase the target cell pool for HIV infection because the virus preferentially infects HIV-specific CD4+ T cells. However, virus-specific CD4+ helper T-cell responses are thought to be important for functional CD8+ cytotoxic-T-lymphocyte (CTL) induction in HIV infection, and it has remained unknown whether HIV-specific memory CD8+ T cells induced by vaccination without HIV-specific CD4+ T-cell help can exert effective responses after virus exposure. Here we show the impact of CD8+ T-cell memory induction without virus-specific CD4+ T-cell help on the control of a simian immunodeficiency virus (SIV) challenge in rhesus macaques. We developed a prophylactic vaccine by using a Sendai virus (SeV) vector expressing a single SIV Gag241-249 CTL epitope fused with enhanced green fluorescent protein (EGFP). Vaccination resulted in induction of SeV-EGFP-specific CD4+ T-cell and Gag241-249-specific CD8+ T-cell responses. After a SIV challenge, the vaccinees showed dominant Gag241-249-specific CD8+ T-cell responses with higher effector memory frequencies in the acute phase and exhibited significantly reduced viral loads. These results demonstrate that virus-specific memory CD8+ T cells induced by vaccination without virus-specific CD4+ T-cell help could indeed facilitate SIV control after virus exposure, indicating the benefit of prophylactic vaccination eliciting virus-specific CTL memory with non-virus-specific CD4+ T-cell responses for HIV control.

scholarly journals Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8+T-Cell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection

2015 ◽  
Vol 89 (21) ◽  
pp. 10802-10820 ◽  
Author(s):  
Mauricio A. Martins ◽  
Damien C. Tully ◽  
Michael A. Cruz ◽  
Karen A. Power ◽  
Marlon G. Veloso de Santana ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Group 1

ABSTRACTCertain major histocompatibility complex class I (MHC-I) alleles (e.g.,HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed “elite controllers” [ECs]). Likewise,Mamu-B*08expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infectedMamu-B*08+animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control inMamu-B*08+macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8+T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8+T-cell response would facilitate the development of elite control inMamu-B*08+animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinatedMamu-B*08+animals withnefinserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8+T cells. These vaccine-induced effector memory CD8+T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8+T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control inMamu-B*08+macaques.IMPORTANCESince elite control of chronic-phase viremia is a classic example of an effective immune response against HIV/SIV, elucidating the basis of this phenomenon may provide useful insights into how to elicit such responses by vaccination. We have previously established that vaccine-induced CD8+T-cell responses against three immunodominant epitopes can increase the incidence of elite control in SIV-infectedMamu-B*08+rhesus macaques—a model of HLA-B*27-mediated elite control. Here, we investigated whether a monotypic vaccine-induced CD8+T-cell response targeting the conserved “late-escaping” Nef RL10 epitope can increase the incidence of elite control inMamu-B*08+monkeys. Surprisingly, vaccine-induced Nef RL10-specific CD8+T cells selected for variants within days after infection and, ultimately, did not facilitate the development of elite control. Elite control is, therefore, likely to involve CD8+T-cell responses against more than one epitope. Together, these results underscore the complexity and multidimensional nature of virologic control of lentivirus infection.

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