Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis

Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100tg) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100. However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4+ T cell hybridomas were MHC class II–restricted and expressed a single T cell receptor (TCR) variable (V) β chain, TRBV31, with different Vα chains. Immunization of huB100tgxLdlr−/− mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4+ T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis.

Download Full-text

ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming

Blood ◽

10.1182/blood-2005-01-0220 ◽

2005 ◽

Vol 106 (1) ◽

pp. 216-223 ◽

Cited By ~ 300

Author(s):

Elodie Segura ◽

Carole Nicco ◽

Bérangère Lombard ◽

Philippe Véron ◽

Graça Raposo ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Naive T Cells ◽

Naïve T Cells ◽

Cell Responses

Exosomes are secreted vesicles formed in late endocytic compartments. Immature dendritic cells (DCs) secrete exosomes, which transfer functional major histocompatibility complex (MHC)–peptide complexes to other DCs. Since immature and mature DCs induce different functional T-cell responses (ie, tolerance versus priming), we asked whether DC maturation also influenced the priming abilities of their exosomes. We show that exosomes secreted by lipopolysaccharide (LPS)–treated mature DCs are 50- to 100-fold more potent to induce antigen-specific T-cell activation in vitro than exosomes from immature DCs. In vitro, exosomes from mature DCs transfer to B lymphocytes the ability to prime naive T cells. In vivo, only mature exosomes trigger effector T-cell responses, leading to fast skin graft rejection. Proteomic and biochemical analyses revealed that mature exosomes are enriched in MHC class II, B7.2, intercellular adhesion molecule 1 (ICAM-1), and bear little milk-fat globule–epidermal growth factor–factor VIII (MFG-E8) as compared with immature exosomes. Functional analysis using DC-derived exosomes from knock-out mice showed that MHC class II and ICAM-1 are required for mature exosomes to prime naive T cells, whereas B7.2 and MFG-E8 are dispensable. Therefore, changes in protein composition and priming abilities of exosomes reflect the maturation signals received by DCs.

Download Full-text

B7-1/B7-2 Costimulation Regulates Plaque Antigen–Specific T-Cell Responses and Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice

Circulation ◽

10.1161/01.cir.0000127121.16815.f1 ◽

2004 ◽

Vol 109 (16) ◽

pp. 2009-2015 ◽

Cited By ~ 101

Author(s):

Chiara Buono ◽

Hong Pang ◽

Yasushi Uchida ◽

Peter Libby ◽

Arlene H. Sharpe ◽

...

Keyword(s):

T Cell ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

T Cell Responses ◽

Low Density ◽

Lipoprotein Receptor ◽

Low Density Lipoprotein Receptor ◽

Cell Responses ◽

Density Lipoprotein Receptor ◽

Deficient Mice

Download Full-text

HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer+ Gag-Specific CD4+ T Cells in Chronic Clade C HIV-1 Infection

Journal of Virology ◽

10.1128/jvi.02477-16 ◽

2017 ◽

Vol 91 (7) ◽

Cited By ~ 10

Author(s):

Faatima Laher ◽

Srinika Ranasinghe ◽

Filippos Porichis ◽

Nikoshia Mewalal ◽

Karyn Pretorius ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Single Class ◽

Cell Responses ◽

Clade C ◽

Hiv Controllers ◽

Hiv 1

ABSTRACT Immune control of viral infections is heavily dependent on helper CD4+ T cell function. However, the understanding of the contribution of HIV-specific CD4+ T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4+ T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4+ T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4+ T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4+ T cells in HIV controllers than progressors (P = 0.0001), and these expanded Gag-specific CD4+ T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control (r = −0.5, P = 0.02). These data identify an association between HIV-specific CD4+ T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4+ T cell responses in natural infections. IMPORTANCE Increasing evidence suggests that virus-specific CD4+ T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4+ T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV infections worldwide. Understanding the contribution of HIV-specific CD4+ T cell responses in clade C infection is particularly important for developing vaccines that would be efficacious in sub-Saharan Africa, where clade C infection is dominant. Here, we employed MHC class II tetramers designed to immunodominant Gag epitopes and used them to characterize CD4+ T cell responses in HIV-1 clade C infection. Our results demonstrate an association between the frequency of HIV-specific CD4+ T cell responses targeting an immunodominant DRB1*11-Gag41 complex and HIV control, highlighting the important contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infections.

Download Full-text

Faculty Opinions recommendation of Peptide-MHC class II dimers as therapeutics to modulate antigen-specific T cell responses in autoimmune diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016402.200705 ◽

2003 ◽

Author(s):

Matthias von Herrath

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Autoimmune Diabetes ◽

T Cell Responses ◽

Class Ii ◽

Cell Responses

Download Full-text

Faculty Opinions recommendation of Cutting edge: Conditional MHC class II expression reveals a limited role for B cell antigen presentation in primary and secondary CD4 T cell responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718020496.793480946 ◽

2013 ◽

Author(s):

Tim Manser

Keyword(s):

T Cell ◽

B Cell ◽

Antigen Presentation ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Cutting Edge ◽

Cd4 T Cell ◽

Cell Antigen ◽

Cell Responses

Download Full-text

DNA Vaccines Encoding Antigen Targeted to MHC Class II Induce Influenza-Specific CD8+ T Cell Responses, Enabling Faster Resolution of Influenza Disease

Frontiers in Immunology ◽

10.3389/fimmu.2016.00321 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 8

Author(s):

Laura Lambert ◽

Ekaterina Kinnear ◽

Jacqueline U. McDonald ◽

Gunnveig Grodeland ◽

Bjarne Bogen ◽

...

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Dna Vaccines ◽

T Cell Responses ◽

Cd8 T Cell ◽

Class Ii ◽

Cell Responses

Download Full-text

Mouse Schwann cells activate MHC class I and II restricted T-cell responses, but require external peptide processing for MHC class II presentation

Neurobiology of Disease ◽

10.1016/j.nbd.2009.11.006 ◽

2010 ◽

Vol 37 (2) ◽

pp. 483-490 ◽

Cited By ~ 20

Author(s):

Gerd Meyer zu Hörste ◽

Holger Heidenreich ◽

Anne K. Mausberg ◽

Helmar C. Lehmann ◽

Anneloor L.M.A. ten Asbroek ◽

...

Keyword(s):

T Cell ◽

Schwann Cells ◽

Mhc Class I ◽

Mhc Class Ii ◽

T Cell Responses ◽

Class Ii ◽

Class I ◽

Peptide Processing ◽

Cell Responses

Download Full-text

Functional interaction between human histocompatibility leukocyte antigen (HLA) class II and mouse CD4 molecule in antigen recognition by T cells in HLA-DR and DQ transgenic mice.

Journal of Experimental Medicine ◽

10.1084/jem.180.1.165 ◽

1994 ◽

Vol 180 (1) ◽

pp. 165-171 ◽

Cited By ~ 21

Author(s):

K Yamamoto ◽

Y Fukui ◽

Y Esaki ◽

T Inamitsu ◽

T Sudo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

T Cell Responses ◽

Class Ii ◽

Hla Class Ii ◽

Functional Interaction ◽

Leukocyte Antigen ◽

Cell Responses ◽

Hla Class Ii Molecules

Studies in vitro have suggested that a species barrier exists in functional interaction between human histocompatibility leukocyte antigen (HLA) class II and mouse CD4 molecules. However, whether mouse CD4+ T cells restricted by HLA class II molecules are generated in HLA class II transgenic mice and respond to peptide antigens across this barrier has remained unclear. In an analysis of T cell responses to synthetic peptides in mice transgenic for HLA-DR51 and -DQ6, we found that DR51 and DQ6 transgenic mice acquired significant T cell response to influenza hemagglutinin-derived peptide 307-319 (HA 307) and Streptococcus pyogenes M12 protein-derived peptide 347-397 (M6C2), respectively. Inhibition studies with several monoclonal antibodies showed that transgenic HLA class II molecules presented these peptides to mouse CD4+ T cells. Furthermore, T cell lines specific for HA 307 or M6C2 obtained from the transgenic mice could respond to the peptide in the context of relevant HLA class II molecules expressed on mouse L cell transfectants that lack the expression of mouse MHC class II. These findings indicate that interaction between HLA class II and mouse CD4 molecules is sufficient for provoking peptide-specific HLA class II-restricted T cell responses in HLA class II transgenic mice.

Download Full-text