RESUMEN

Chronic infections induce CD4+ T-cells with cytotoxic functions (CD4 CTLs); at present, it is still unknown whether latent tuberculosis (LTB) and active tuberculosis (ATB) induce CD4 CTLs. Plasma and cells from four patient groups-uninfected contact (UC), LTB, and ATB (divided as sensitive [DS-TB]- or resistant [DR-TB]-drug)-were evaluated by flow cytometry, q-PCR, and proteomics. The data showed that ATB patients had an increased frequency of CD4+ T-cells and a decreased frequency of CD8+ T-cells. The latter displays an exhausted-like profile characterized by CD39, CD279, and TIM-3 expression. ATB had a high frequency of CD4 + perforin+ cells, suggesting a CD4 CTL profile. The expression (at the transcriptional level) of granzyme A, granzyme B, granulysin, and perforin, as well as the genes T-bet (Tbx21) and NKG2D (Klrk1), in enriched CD4+ T-cells, confirmed the cytotoxic signature of CD4+ T-cells during ATB (which was stronger in DS-TB than in DR-TB). Moreover, proteomic analysis revealed the presence of HSP70 (in DS-TB) and annexin A5 (in DR-TB), which are molecules that have been associated with favoring the CD4 CTL profile. Finally, we found that lipids from Mycobacterium tuberculosis increased the presence of CD4 CTLs in DR-TB patients. Our data suggest that ATB is characterized by exhausted-like CD8+ T-cells, which, together with a specific microenvironment, favor the presence of CD4 CTLs.

Asunto(s)

Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Granzimas , Receptor 2 Celular del Virus de la Hepatitis A , Perforina , Tuberculosis , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Masculino , Granzimas/metabolismo , Granzimas/genética , Granzimas/inmunología , Perforina/metabolismo , Perforina/genética , Perforina/inmunología , Adulto , Femenino , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Tuberculosis/inmunología , Tuberculosis/microbiología , Tuberculosis Latente/inmunología , Tuberculosis Latente/microbiología , Persona de Mediana Edad , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Mycobacterium tuberculosis/inmunología , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Antígenos CD/metabolismo , Antígenos CD/inmunología , Antígenos CD/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Proteómica/métodos , Antígenos de Diferenciación de Linfocitos T , Apirasa