ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis.
Airways infection with Mycobacterium tuberculosis (Mtb) is contained mostly by T cell responses, however, Mtb has developed evasion mechanisms which affect antigen presenting cell (APC) maturation/recruitment delaying the onset of Ag-specific T cell responses. Hypothetically, bypassing the natural infection routes by delivering antigens directly to APCs may overcome the pathogen's naturally evolved evasion mechanisms, thus facilitating the induction of protective immune responses. We generated a murine monoclonal fusion antibody (α-DEC-ESAT) to deliver Early Secretory Antigen Target (ESAT)-6 directly to DEC205+ APCs and to assess its in vivo effects on protection associated responses (IFN-γ production, in vivo CTL killing, and pulmonary mycobacterial load). Treatment with α-DEC-ESAT alone induced ESAT-6-specific IFN-γ producing CD4+ T cells and prime-boost immunization prior to Mtb infection resulted in early influx (d14 post-infection) and increased IFN-γ+ production by specific T cells in the lungs, compared to scarce IFN-γ production in control mice. In vivo CTL killing was quantified in relevant tissues upon transferring target cells loaded with mycobacterial antigens. During infection, α-DEC-ESAT-treated mice showed increased target cell killing in the lungs, where histology revealed cellular infiltrate and considerably reduced bacterial burden. Targeting the mycobacterial antigen ESAT-6 to DEC205+ APCs before infection expands specific T cell clones responsible for early T cell responses (IFN-γ production and CTL activity) and substantially reduces lung bacterial burden. Delivering mycobacterial antigens directly to APCs provides a unique approach to study in vivo the role of APCs and specific T cell responses to assess their potential anti-mycobacterial functions.
Department of Cell Biology, Cinvestav-IPN, Ciudad de México, Mexico; Department of Immunology, ENCB-IPN, Ciudad de México, Mexico.
Aarón
A
Silva-Sánchez
Department of Cell Biology, Cinvestav-IPN, Ciudad de México, Mexico; Department of Immunology, ENCB-IPN, Ciudad de México, Mexico.
Selene
S
Meza-Pérez
Physiology and Cell Biology, Rockefeller University, New York, New York, United States of America.
Adriana
A
Flores-Langarica
Department of Cell Biology, Cinvestav-IPN, Ciudad de México, Mexico.
Luis
L
Donis-Maturano
Department of Immunology, ENCB-IPN, Ciudad de México, Mexico.
Iris
I
Estrada-García
Department of Cell Biology, Cinvestav-IPN, Ciudad de México, Mexico.
Juana
J
Calderón-Amador
Department of Pathology INNSZ, Ciudad de México, Mexico.
Rogelio
R
Hernández-Pando
Physiology and Cell Biology, Rockefeller University, New York, New York, United States of America.
Juliana
J
Idoyaga
Physiology and Cell Biology, Rockefeller University, New York, New York, United States of America.
Ralph M
RM
Steinman
Department of Cell Biology, Cinvestav-IPN, Ciudad de México, Mexico.
Leopoldo
L
Flores-Romo
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D010455:Peptides / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology
D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D015703:Antigens, CD; D001426:Bacterial Proteins; C093569:DEC-205 receptor; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma