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

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.

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Alloreactive T Cell Responses and Acute Rejection of Single Class II MHC-Disparate Heart Allografts Are under Strict Regulation by CD4+CD25+ T Cells.

The Journal of Immunology ◽

10.4049/jimmunol.174.8.5135-a ◽

2005 ◽

Vol 174 (8) ◽

pp. 5135.2-5135 ◽

Cited By ~ 1

Author(s):

Soren Schenk ◽

Danielle D. Kish ◽

Chunshui He ◽

Tarek El-Sawy ◽

Eise Chiffoleau ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Acute Rejection ◽

T Cell Responses ◽

Class Ii ◽

Single Class ◽

Cell Responses ◽

Class Ii Mhc ◽

Strict Regulation ◽

Alloreactive T Cell

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

Journal of Experimental Medicine ◽

10.1084/jem.20092243 ◽

2010 ◽

Vol 207 (5) ◽

pp. 1081-1093 ◽

Cited By ~ 154

Author(s):

Andreas Hermansson ◽

Daniel F.J. Ketelhuth ◽

Daniela Strodthoff ◽

Marion Wurm ◽

Emil M. Hansson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

T Cell Responses ◽

Class Ii ◽

Low Density ◽

Cell Responses ◽

Ldl Particles

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.

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Identical peptides recognized by MHC class I- and II-restricted T cells.

Journal of Experimental Medicine ◽

10.1084/jem.170.1.279 ◽

1989 ◽

Vol 170 (1) ◽

pp. 279-289 ◽

Cited By ~ 33

Author(s):

D L Perkins ◽

M Z Lai ◽

J A Smith ◽

M L Gefter

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Responses ◽

Class Ii ◽

Antigen Recognition ◽

Class I ◽

Single Class ◽

Mhc Molecules ◽

Cell Responses ◽

Class Ii Mhc

Previous data from many groups show that both class I and class II-restricted T cells recognize short synthetic peptides in the context of their respective MHC molecules (9-18), all of the peptides described to date are restricted to only a single class of MHC molecules; however, structural homology between the class I and II MHC molecules and the use of similar TCRs by class I and II-restricted T cells suggest that antigen recognition mechanisms are similar in both systems. To directly compare antigen recognition in the two systems, we analyzed peptides for the ability to function in both a class I and II-restricted system and found that seven of seven individual peptides tested stimulate both class I and II-restricted T cell responses. In addition, two of the peptides can function in different species stimulating both human class I and murine class II T cell responses. Thus, the process of T cell recognition of antigen in the context of MHC molecules was highly conserved in evolution not only between the class I and class II MHC systems, but also between the murine and human species.

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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.

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Alloreactive T Cell Responses and Acute Rejection of Single Class II MHC-Disparate Heart Allografts Are under Strict Regulation by CD4+CD25+ T Cells

The Journal of Immunology ◽

10.4049/jimmunol.174.6.3741 ◽

2005 ◽

Vol 174 (6) ◽

pp. 3741-3748 ◽

Cited By ~ 62

Author(s):

Soren Schenk ◽

Danielle D. Kish ◽

Chunshui He ◽

Tarek El-Sawy ◽

Eise Chiffoleau ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Acute Rejection ◽

T Cell Responses ◽

Class Ii ◽

Single Class ◽

Cell Responses ◽

Class Ii Mhc ◽

Strict Regulation ◽

Alloreactive T Cell

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HIV Controllers with HLA-DRB113 and HLA-DQB106 Alleles Have Strong, Polyfunctional Mucosal CD4+ T-Cell Responses

Journal of Virology ◽

10.1128/jvi.00980-10 ◽

2010 ◽

Vol 84 (21) ◽

pp. 11020-11029 ◽

Cited By ~ 75

Author(s):

April L. Ferre ◽

Peter W. Hunt ◽

Delandy H. McConnell ◽

Megan M. Morris ◽

Juan C. Garcia ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Interleukin 2 ◽

Rectal Mucosa ◽

T Cell Responses ◽

Class Ii ◽

T Cell Response ◽

Cell Responses ◽

Hiv Controllers

ABSTRACT A small percentage of human immunodeficiency virus (HIV)-infected individuals, termed elite controllers, are able to spontaneously control HIV replication in blood. As the gastrointestinal mucosa is an important site of HIV transmission and replication as well as CD4+ T-cell depletion, it is important to understand the nature of the immune responses occurring in this compartment. Although the role of the HIV-specific CD8+ T-cell responses in mucosal tissues has been described, few studies have investigated the role of mucosal HIV-specific CD4+ T cells. In this study, we assessed HIV-specific CD4+ T-cell responses in the rectal mucosa of 28 “controllers” (viral load [VL] of <2,000 copies/ml), 14 “noncontrollers” (VL of >10,000 copies/ml), and 10 individuals on highly active antiretroviral therapy (HAART) (VL of <75 copies/ml). Controllers had higher-magnitude Gag-specific mucosal CD4+ T-cell responses than individuals on HAART (P < 0.05), as measured by their ability to produce gamma interferon (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and macrophage inflammatory protein 1β (MIP-1β). The frequency of polyfunctional mucosal CD4+ T cells was also higher in controllers than in noncontrollers or individuals on HAART (P < 0.05). Controllers with the strongest HIV-specific CD4+ T-cell responses possessed class II HLA alleles, HLA-DRB1*13 and/or HLA-DQB1*06, previously associated with a nonprogression phenotype. Strikingly, individuals with both HLA-DRB1*13 and HLA-DQB1*06 had highly polyfunctional mucosal CD4+ T cells compared to individuals with HLA-DQB1*06 alone or other class II alleles. The frequency of polyfunctional CD4+ T cells in rectal mucosa positively correlated with the magnitude of the mucosal CD8+ T-cell response (Spearman's r = 0.43, P = 0.005), suggesting that increased CD4+ T-cell “help” may be important in maintaining strong CD8+ T-cell responses in the gut of HIV controllers.

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