HIV-Infected Dendritic Cells Present Endogenous MHC Class II-Restricted Antigens to HIV-Specific CD4+ T Cells.
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.
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, F-75013 Paris, France;
Pierre-Grégoire
PG
Coulon
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, F-75013 Paris, France;
Clémence
C
Richetta
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, F-75013 Paris, France;
Angéline
0000-0002-8437-3204
A
Rouers
CNRS, FRE3689, Université de Montpellier, Centre d'Études d'Agents Pathogènes et Biotechnologies pour la Santé, 34293 Montpellier, France;
Fabien P
0000-0003-3168-0697
FP
Blanchet
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, F-75013 Paris, France;
Alejandra
0000-0003-4101-5834
A
Urrutia
Unité de Génomique Virale et Vaccination, Institut Pasteur, 75724 Paris, France;
Mathilde
M
Guerbois
Department of Dermatology and Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
Vincent
0000-0001-6079-4517
V
Piguet
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, F-75013 Paris, France; Département d'Immunologie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, 75013 Paris, France; and.
Ioannis
I
Theodorou
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, F-75013 Paris, France;
Anne
0000-0002-5699-2745
A
Bet
Unité Virus et Immunité, Institut Pasteur, 75724 Paris, France.
Olivier
O
Schwartz
Unité de Génomique Virale et Vaccination, Institut Pasteur, 75724 Paris, France;
Frédéric
F
Tangy
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, F-75013 Paris, France;
Stéphanie
0000-0001-7273-3930
S
Graff-Dubois
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, F-75013 Paris, France;
Sylvain
S
Cardinaud
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses, U1135, CNRS 8255, F-75013 Paris, France; Département d'Immunologie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, 75013 Paris, France; and arnaud.moris@upmc.fr.
Arnaud
0000-0002-5052-1678
A
Moris
D017951:Antigen Presentation / Q000276:immunology*; D001343:Autophagy / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D018613:Microscopy, Confocal
D000949:Histocompatibility Antigens Class II