Tim-3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients.
BACKGROUND
T cell immunoglobulin and mucin domain (Tim) 3 and programmed death 1 (PD-1) are co-inhibitory receptors involved in the so-called T cell exhaustion, and in vivo blockade of these molecules restores T cell dysfunction. High expression of Tim-3 and PD-1 is induced after chronic antigen-specific stimulation of T cells during HIV infection. We have previously demonstrated that the interaction of Tim-3 with its ligand galectin-9 induces macrophage activation and killing of Mycobacterium tuberculosis. Our aim in this study was to analyze the Tim-3 expression profile before and after six months of antiretroviral therapy and the impact of Tim-3 and PD-1 blocking on immunity against M. tuberculosis.


METHODS
HIV+ patients naïve to anti-retroviral therapy (ART) were followed up for six months. Peripheral immune-cell phenotype (CD38/HLA-DR/galectin-9/Tim-3 and PD-1) was assessed by flow cytometry. Supernatants were analyzed with a multiplex cytokine detection system (human Th1/Th2 cytokine Cytometric Bead Array) by flow cytometry. Control of bacterial growth was evaluated by using an in vitro experimental model in which virulent M. tuberculosis-infected macrophages were cultured with T cells in the presence or absence of Tim-3 and PD-1 blocking antibodies. Interleukin-1 beta treatment of infected macrophages was evaluated by enumerating colony-forming units.


RESULTS
We showed that HIV+ patients had an increased expression of Tim-3 in T cells and were able to control bacterial growth before ART administration. By blocking Tim-3 and PD-1, macrophages and T cells recovered their functionality and had a higher ability to control bacterial growth; this result was partially dependent on the restitution of cytokine production.


CONCLUSIONS
In this study, we demonstrated that increased Tim-3 expression can limit the ability of the immune system to control the infection of intracellular bacteria such as M. tuberculosis. The use of ART and the in vitro manipulation of the Tim-3 and PD-1 molecules restored the functionality of T cells and macrophages to restrict bacterial growth. Our results provide a novel immune strategy that may be implemented in the near future in order to improve the immune responses in HIV+ patients.
Laboratorio de Inmunología IntegrativaInstituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Distrito Federal, México; isadamx@iner.gob.mx.
Isabel
I
Sada-Ovalle
Laboratorio de Inmunología IntegrativaInstituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Distrito Federal, México.
Ranferi
R
Ocaña-Guzman
Departamento de Infectología del Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Distrito Federal, México.
Santiago
S
Pérez-Patrigeón
Laboratorio de Inmunología IntegrativaInstituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Distrito Federal, México.
Leslie
L
Chávez-Galán
Departamento de Infectología del Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Distrito Federal, México.
Juan
J
Sierra-Madero
Laboratorio de Inmunología IntegrativaInstituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Distrito Federal, México.
Luis
L
Torre-Bouscoulet
Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|German Center for Infection Research, Partner Site Standort Hamburg-Lübeck-Borstel.
Marylyn M
MM
Addo
D017088:AIDS-Related Opportunistic Infections / Q000276:immunology*; D000328:Adult; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000502:physiology*; D014376:Tuberculosis / Q000150:complications / Q000276:immunology*
C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
HIV; PD-1; Tim-3; galectin 9; tuberculosis