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.
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Granzymes , Hepatitis A Virus Cellular Receptor 2 , Perforin , Tuberculosis , Humans , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Male , Granzymes/metabolism , Granzymes/genetics , Granzymes/immunology , Perforin/metabolism , Perforin/genetics , Perforin/immunology , Adult , Female , Hepatitis A Virus Cellular Receptor 2/metabolism , Hepatitis A Virus Cellular Receptor 2/immunology , Tuberculosis/immunology , Tuberculosis/microbiology , Latent Tuberculosis/immunology , Latent Tuberculosis/microbiology , Middle Aged , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Mycobacterium tuberculosis/immunology , T-Box Domain Proteins/metabolism , T-Box Domain Proteins/genetics , T-Box Domain Proteins/immunology , Antigens, CD/metabolism , Antigens, CD/immunology , Antigens, CD/genetics , NK Cell Lectin-Like Receptor Subfamily K/metabolism , NK Cell Lectin-Like Receptor Subfamily K/immunology , NK Cell Lectin-Like Receptor Subfamily K/genetics , Proteomics/methods , Antigens, Differentiation, T-Lymphocyte , Apyrase
Resumen La leucemia linfoblástica aguda es el tipo de leucemia más frecuente en niños entre los 2 y 3 años. A nivel internacional la población hispana es reportada como la más prevalente. En México se carece de información reciente, sin embargo, se conoce que es uno de los cánceres más frecuentes en niños. La infiltración de células linfoblásticas a sistema nervioso central es una complicación de pronóstico ominoso que puede presentarse en los pacientes con leucemia linfoblástica aguda, actualmente el diagnóstico se establece mediante citología de líquido cefalorraquídeo, sin embargo, es una prueba operador dependiente y que es afectada por el número de punciones realizadas en la toma de líquido cefalorraquídeo, con potencial contaminación con sangre. En distintos estudios se han caracterizado 6 genes que presentan una sobreexpresión en líquido cefalorraquídeo cuando se presenta dicha infiltración, en esta revisión analizamos estos nuevos marcadores y su potencial como herramientas de diagnóstico oportuno.
Abstract Acute lymphoblastic leukemia is the most common type of leukemia in children between 2 and 3 years of age. Internationally, hispanic population is reported as the most prevalent. In Mexico there is few recent information, however, it is known that it is one of the most frequent cancers in children. Infiltration of lymphoblastic cells into the central nervous system is an ominous prognostic complication that can occur in patients with acute lymphoblastic leukemia. Currently, diagnosis is established by cerebrospinal fluid cytology, however, this technique is affected by the number of punctions done while obtaining the fluid. In several research studies, 6 genes have been identified to be overexpressed in cerebrospinal fluid when infiltration occurs. In this review we analyzed these new molecular biomarkers and their potential as tools for timely diagnosis.
