Modulation of NKG2D expression in human CD8(+) T cells corresponding with tuberculosis drug cure.
BACKGROUND
Biomarkers predicting tuberculosis treatment response and cure would facilitate drug development. This study investigated expression patterns of the co-stimulation molecule NKG2D in human tuberculosis and treatment to determine its potential usefulness as a host biomarker of tuberculosis drug efficacy.


METHODS
Tuberculosis patients (n = 26) were recruited in Lahore, Pakistan, at diagnosis and followed up during treatment. Household contacts (n = 24) were also recruited. NKG2D expression was measured by qRT-PCR in RNA samples both ex vivo and following overnight mycobacterial stimulation in vitro. Protein expression of NKG2D and granzyme B was measured by flow cytometry.


RESULTS
NKG2D expression in newly diagnosed tuberculosis patients was similar to household contacts in ex vivo RNA, but was higher following in vitro stimulation. The NKG2D expression was dramatically reduced by intensive phase chemotherapy, in both ex vivo blood RNA and CD8(+) T cell protein expression, but then reverted to higher levels after the continuation phase in successfully treated patients.


CONCLUSIONS
The changes in NKG2D expression through successful treatment reflect modulation of the peripheral cytotoxic T cell response. This likely reflects firstly in vivo stimulation by live Mycobacterium tuberculosis, followed by the response to dead bacilli, antigen-release and finally immunopathology resolution. Such changes in host peripheral gene expression, alongside clinical and microbiological indices, could be developed into a biosignature of tuberculosis drug-induced cure to be used in future clinical trials.
Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Syeda S
SS
Hassan
Jang-Eun
JE
Cho
Muhammad
M
Akram
Katherine L
KL
Fielding
Hazel M
HM
Dockrell
Jacqueline M
JM
Cliff
D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D014376:Tuberculosis / Q000188:drug therapy* / Q000235:genetics*; D055815:Young Adult
D000995:Antitubercular Agents; C120528:HCST protein, human; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D012333:RNA, Messenger; D011971:Receptors, Immunologic