Toward a Network Model of MHC Class II-Restricted Antigen Processing

Miller, Michael A.; Ganesan, Asha Purnima Veerappan; Eisenlohr, Laurence C.

doi:10.3389/fimmu.2013.00464

Cited by 13 publications

(12 citation statements)

References 143 publications

(128 reference statements)

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“…In a more recent study, Miller et al (15) showed that initiation of CD4 + T cell responses to influenza virus is driven predominantly by endogenous Ags expressed within the infected APC. Taken together, these findings challenge the notion that a single epitope's fate is sealed by its origin, and, instead, they indicate that commitment to its processing or presentation pathways depends on the Ag source, localization, and type of APC (16,17).…”

Section: A Ccumulating Evidence Suggests That Hiv-specific (Hs) Cd4contrasting

confidence: 47%

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

Coulon

Richetta

Rouers

et al. 2016

The Journal of Immunology

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It is widely assumed that CD4+ T cells recognize antigenic peptides (epitopes) derived solely from incoming, exogenous, viral particles or proteins. However, alternative sources of MHC class II (MHC-II)–restricted Ags have been described, in particular epitopes derived from newly synthesized proteins (so-called endogenous). In this study, we show that HIV-infected dendritic cells (DC) present MHC-II–restricted endogenous viral Ags to HIV-specific (HS) CD4+ T cells. This endogenous pathway functions independently of the exogenous route for HIV Ag presentation and offers a distinct possibility for the immune system to activate HS CD4+ T cells. We examined the implication of autophagy, which plays a crucial role in endogenous viral Ag presentation and thymic selection of CD4+ T cells, in HIV endogenous presentation. We show that infected DC do not use autophagy to process MHC-II–restricted HIV Ags. This is unlikely to correspond to a viral escape from autophagic degradation, as infecting DC with Nef- or Env-deficient HIV strains did not impact HS T cell activation. However, we demonstrate that, in DC, specific targeting of HIV Ags to autophagosomes using a microtubule-associated protein L chain 3 (LC3) fusion protein effectively enhances and broadens HS CD4+ T cell responses, thus favoring an endogenous MHC-II–restricted presentation. In summary, in DC, multiple endogenous presentation pathways lead to the activation of HS CD4+ T cell responses. These findings will help in designing novel strategies to activate HS CD4+ T cells that are required for CTL activation/maintenance and B cell maturation.

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Section: A Ccumulating Evidence Suggests That Hiv-specific (Hs) Cd4contrasting

confidence: 47%

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

Coulon

Richetta

Rouers

et al. 2016

The Journal of Immunology

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“…For many years alternatives to the classical MHC-II processing pathway have been recognized. These include loading of “recycling” MHC-II in an early endosomal compartment [56–58] and endogenous processing, in which peptide is derived from antigen synthesized within the APC, often via processing mechanisms that extend beyond the endocytic compartment [59]. Until recently, these alternatives have been considered marginal.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent work from our laboratory suggests that peptides derived from endogenous processing drive the vast majority of the response to infectious influenza [60*]. Furthermore, we have observed endogenous processing to be comprised of an array of pathways, sufficiently complex for us to propose the term “processing network” [59, 60*]. Recently, a similar level of complexity has been reported for the extra-endosomal generation of the human MHC-II-restricted self-peptidome [61*].…”

Section: Discussionmentioning

confidence: 99%

Giving CD4+ T cells the slip: viral interference with MHC class II-restricted antigen processing and presentation

Forsyth

Eisenlohr

2016

Current Opinion in Immunology

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Activation of CD4+ T cells through interactions with peptides bound to Major Histocompatibility Complex Class II (MHC-II) molecules is a crucial step in clearance of most pathogens. Consequently, many viruses have evolved ways of blocking this aspect of adaptive immunity, from specific targeting of processing and presentation components to modulation of signaling pathways that regulate peptide presentation in addition to many other host defense mechanisms. Such cases of interference are far less common compared to what has been elucidated in MHC-I processing and presentation. This may be attributable in part to the complexity of MHC-II antigen processing, the scope of which is only now coming to light.

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“…Though elucidation of the exact mechanisms that generate self-pMHC able to mediate thymic selection is ongoing, it is clear they are complicated in nature and challenge our current understanding of antigen processing. Involvement of antigen processing machinery outside of the “classical” pathways may prove to play a vital role in establishing the selecting ligandome that leads to functional and self-tolerant CD4 and CD8 T cell repertoires (Miller et al, 2013). Unequivocal determination of which model, or more likely, combination of models, most accurately reflects in vivo thymocyte selection depends intimately upon gaining an understanding of the landscape of selecting self-pMHC complex expression.…”

Section: Introductionmentioning

confidence: 99%

Self-pMHCII complexes are variably expressed in the thymus and periphery independent of mRNA expression but dependent on the activation state of the APCs

Rodriguez

Jiang

Bujo

et al. 2015

Molecular Immunology

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Self-peptide MHCII ligands are critical for selection of CD4+ T cells in the thymus, and maintenance in the periphery. To date, no investigation as to the exact thymic and peripheral expression of a naturally occurring positive selecting self-peptide MHCII (self-pMHCII) complex has taken place. We have generated a sensitive T cell hybridoma to functionally detect the endogenous presentation of a confirmed positive selecting self-pMHCII complex for a CD4+ transgenic T cell. Using this tool to survey and quantify the expression selecting self-pMHCII, we have shown unequivocal proof that a known CD4+ selecting ligand can be presented on both positive and negative selecting thymic APCs. We also show that peripheral presentation of this same selecting ligand is affected by activation state of the APCs. Furthermore, discrepancies between the gene expression and self-pMHCII complex presentation of this bona fide selecting ligand suggest that functional detection self-ligand complexes will be required to establish a complete view of the naturally presented endogenous self-pMHC landscape.

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Toward a Network Model of MHC Class II-Restricted Antigen Processing

Cited by 13 publications

References 143 publications

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

Giving CD4+ T cells the slip: viral interference with MHC class II-restricted antigen processing and presentation

Self-pMHCII complexes are variably expressed in the thymus and periphery independent of mRNA expression but dependent on the activation state of the APCs

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